U.S. patent application number 17/170161 was filed with the patent office on 2021-06-03 for topical retinoid compositions.
The applicant listed for this patent is DR. REDDY'S LABORATORIES LTD.. Invention is credited to Manish M. Bankar, Sujit Kumar Dolai, Sateesh Kandavilli, Franklin Okumu.
Application Number | 20210161875 17/170161 |
Document ID | / |
Family ID | 1000005399389 |
Filed Date | 2021-06-03 |
United States Patent
Application |
20210161875 |
Kind Code |
A1 |
Kandavilli; Sateesh ; et
al. |
June 3, 2021 |
TOPICAL RETINOID COMPOSITIONS
Abstract
The present application relates to topical compositions. In
particular, the present application relates to a topical
composition comprising retinoid as active agent, and
pharmaceutically acceptable excipient(s), and a process of
preparing such compositions. Further, the present application
relates to method of using topical compositions for the treatment
of skin disorders such as acne, rosacea, psoriasis etc.
Inventors: |
Kandavilli; Sateesh;
(Plainsboro, NJ) ; Okumu; Franklin; (Morristown,
NJ) ; Bankar; Manish M.; (Nagpur, IN) ; Dolai;
Sujit Kumar; (Ganjam, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DR. REDDY'S LABORATORIES LTD. |
Hyderabad |
|
IN |
|
|
Family ID: |
1000005399389 |
Appl. No.: |
17/170161 |
Filed: |
February 8, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16369320 |
Mar 29, 2019 |
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17170161 |
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15902635 |
Feb 22, 2018 |
10716781 |
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16369320 |
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15621325 |
Jun 13, 2017 |
9931328 |
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15902635 |
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15209716 |
Jul 13, 2016 |
9707216 |
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15621325 |
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62191937 |
Jul 13, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61Q 19/02 20130101;
A61K 8/49 20130101; A61P 17/00 20180101; A61C 19/08 20130101; A61C
19/00 20130101; A61K 8/498 20130101; A61K 9/122 20130101; A61K
31/4436 20130101; A61K 8/671 20130101; A61K 31/7004 20130101; A61Q
19/10 20130101; A61P 17/10 20180101; A61Q 19/08 20130101; A61K
8/678 20130101; A61K 31/355 20130101; A61K 9/0014 20130101; A61Q
19/00 20130101 |
International
Class: |
A61K 31/4436 20060101
A61K031/4436; A61K 8/67 20060101 A61K008/67; A61K 9/00 20060101
A61K009/00; A61K 9/12 20060101 A61K009/12; A61K 8/49 20060101
A61K008/49; A61Q 19/00 20060101 A61Q019/00; A61Q 19/02 20060101
A61Q019/02; A61Q 19/08 20060101 A61Q019/08; A61Q 19/10 20060101
A61Q019/10; A61P 17/10 20060101 A61P017/10; A61P 17/00 20060101
A61P017/00; A61C 19/00 20060101 A61C019/00; A61C 19/08 20060101
A61C019/08; A61K 31/355 20060101 A61K031/355; A61K 31/7004 20060101
A61K031/7004 |
Claims
1. A topical lotion composition, comprising: a) a retinoid
compound; b) an oil phase comprising one or more water immiscible
substances; c) a hydrophilic phase comprising water; d) a
thickener; e) one or more dermatologically acceptable excipient;
and f) one or more surfactants in the range from about 0.01% w/w to
about 10% w/w of the total weight of the composition; wherein the
composition is free of propellant, and wherein the composition has
pH from about 4 to about 7.
2. The topical composition of claim 1, wherein said retinoid
compound is selected from tretinoin, isotretinoin, acitretin,
tazarotene, and adapalene.
3. The topical composition of claim 1, wherein the retinoid
compound is tazarotene.
4. The composition of claim 1, wherein the retinoid compound is
tretinoin.
5. The topical composition of claim 1, wherein the thickener is
selected from carbomers, polyvinyl pyrrolidone, locust gum,
polyvinyl alcohol, cross-linked polyacrylate polymer, guar gum,
locust bean gum, polysaccharides, cellulose polymers and any
combinations thereof.
6. The topical composition of claim 1, wherein the thickener is the
range of from 0.01% to 2%.
7. The topical composition of claim 1, wherein the thickener
comprises a carbomer.
8. The composition of claim 1, wherein the composition excludes
peanut oil.
9. A topical lotion composition comprising: a) a retinoid compound;
b) at least one thickener comprising carbomer; c) at least one
preservative selected from the group consisting of benzyl alcohol,
methylparaben, and combinations thereof; d) an antioxidant
comprising butylated hydroxytoluene; e) a moisturizer comprising
glycerin; f) an emollient comprising mineral oil; g) a pH adjusting
agent comprising trolamine; h) water; and i) one or more
surfactants in the range from about 0.01% w/w to about 10% w/w of
the total weight of the composition; wherein the composition is
free of propellant, and wherein the composition has pH from about 4
to about 7.
10. The topical composition of claim 9, wherein said retinoid
compound is selected from tretinoin, isotretinoin, acitretin,
tazarotene, and adapalene.
11. The composition of claim 1, wherein the retinoid compound is
tretinoin.
12. The topical composition of claim 9, wherein the composition
comprises at least about 60% w/w water based on the total weight of
the composition.
13. The composition of claim 9, comprising one or more surfactants
having a hydrophilic/lipophilic balance (HLB) of more than 10.
14. The composition of claim 9, wherein the surfactants excludes
surfactants selected from cetyl alcohol and stearyl alcohol.
15. The composition of claim 9, wherein the composition excludes
peanut oil.
16. The topical composition of claim 9, wherein the composition has
viscosity in the range of from about 1000 cps to about 50,000 cps,
when measured by Brookfield DV-II pro Viscometer with low viscosity
spindle no. 4 at 20 rpm.
17. A topical lotion composition comprising: a) a retinoid
compound; b) an oil phase comprising one or more water immiscible
substances; c) a hydrophilic phase comprising water; d) a
thickener; and e) one or more dermatologically acceptable
excipient; wherein the composition is free of propellant; wherein
the thickener is selected from carbomers, polyvinyl pyrrolidone,
locust gum, polyvinyl alcohol, cross-linked polyacrylate polymer,
guar gum, locust bean gum, polysaccharides, cellulose polymers and
any combinations thereof; and wherein a substantial amount of
retinoid compound is in hydrophilic phase.
18. The topical composition of claim 17, wherein said retinoid
compound is selected from tretinoin, isotretinoin, acitretin,
tazarotene, and adapalene.
19. The topical composition of claim 17, wherein the retinoid
compound is suspended in the composition.
20. The topical composition of claim 17, wherein D90 globule size
of oil phase is at least 2 microns and less than about 50 microns.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/369,320, filed Mar. 29, 2019, which claims
priority to Ser. No. 15/902,635, filed Feb. 22, 2018, which claims
priority to U.S. patent application Ser. No. 15/621,325, filed Jun.
13, 2017, now issued as U.S. Pat. No. 9,931,328, which claims
priority to U.S. patent application Ser. No. 15/209,716, filed Jul.
13, 2016, now issued as U.S. Pat. No. 9,707,216, which claims
priority from U.S. Provisional Application Ser. No. 62/191,937,
filed Jul. 13, 2015, the entire disclosures of which are
incorporated herein by this reference.
FIELD OF THE INVENTION
[0002] The present application relates to a retinoid-containing
topical composition.
BACKGROUND
[0003] Retinoid compounds are often used in the treatment of
various skin disorders such as acne, psoriasis and like and are
available both as naturally-occurring and synthetic derivatives.
The naturally-occurring retinoid(s) are derived from Vitamin A;
examples are tretinoin (all trans retinoic acid), retinol, retinal
and the like. The synthetic retinoid(s) are small chemical
molecules that act on retinoic acid receptors (RARs) like naturally
occurring retinoid(s); examples of synthetic derivatives are
acitretin, tazarotene, and adapalene and the like.
[0004] Tretinoin (Formula I) is one of the naturally-occurring
retinoids, and is also known as "all trans retinoic acid".
Tretinoin is approved worldwide in topical dosage forms such as
gel, cream and the like, for the treatment of acne vulgaris.
##STR00001##
[0005] Tazarotene (Formula II) is a synthetic derivative, which
acts on retinoic acid receptors (RARs) and is a prodrug that is
converted into its active form, tazarotenic acid, by rapid
deesterification.
##STR00002##
[0006] These retinoids are widely used in various topical dosage
forms having the advantage of the ease of their administration to
the target site. Generally, skin disorders such as acne are treated
by the topical administration of active compounds.
[0007] Acne vulgaris is one of the common skin disorders that
affect the skin's oil glands. The small holes in the skin (pores)
connect to oil glands under the skin. These glands make an oily
substance called sebum. Pores of the skin are connected to the
glands through a canal called a follicle. Acne is thought to be
caused by multiple factors such as overproduction of oil in the
skin called sebum, which is increased under the influence of
hormones. When the follicle of a skin gland clogs up, it causes
inflammation, and thus a pimple grows. Acne affects 85-100% of
people at some point in their lives. The most common acne locations
include face, neck, chest, and back, where most of the sebaceous
glands are located resulting in psychological and social
problems.
[0008] The currently-available compositions for treating acne
include 1) Topical tretinoin; 2) Topical clindamycin alone or in
combination with tretinoin and benzoyl peroxide; 3) Oral
minocycline; 4) Topical adapalene; 5) Topical tazarotene; 6)
Topical benzoyl peroxide alone or in combination with other drugs,
and more. Topical retinoid treatment is a promising therapy for the
treatment of acne; however the main shortcoming in topical
retinoids is that they may cause irritation at the site of
administration. Long term application of topical retinoids to the
patient's skin causes local irritation.
[0009] Generally, topical wash compositions have a profound effect
in acne treatment. The cleansing effects of these compositions
involve eliminating dirt and dead cells, clearing up acne blemishes
and black heads, and preventing the development of new acne
pimples. The ideal skin wash composition removes surface oils
derived from sebaceous glands, and associated debris, without
affecting natural constitutive lipids of skin. Most of the
detergent-/soap-containing skin-cleansing compositions have the
tendency to affect the natural lipid structure of the skin, or
cause dryness to the skin, and some of the facial wash compositions
cause greasy feel to the skin. On the other hand, therapeutic
retinoids cause irritation to the patient's skin. These
skin-cleansing compositions are being offered either as clear
liquids, or as opaque base creams and gels.
[0010] U.S. Pat. No. 7,465,461 discloses a method of enhancing
moisture or reducing dryness using wet skin treatment composition
that leaves the skin feeling clean, but non-greasy.
[0011] U.S. Pat. No. 6,017,938 discloses a method of treating acne
using short-term contact with an acetylenic retinoid, preferably
tazarotene and related compounds.
[0012] U.S. Pat. No. 6,048,902 discloses a method of treating
psoriasis by short-term contact of a topically-applied retinoid
composition.
[0013] US patent application 2010/0098776 discloses soap-based
liquid body and facial wash compositions comprising an
antimicrobial agent. Soap-based liquid composition enhances
antimicrobial deposition in the skin.
[0014] It is found that the topical composition of the present
application comprising a retinoid compound improves skin disorders
such as acne or psoriasis by alleviating both inflamed and
non-inflamed lesions and the administration of this composition
provides more retinoid deposition and less irritation to the
subject's skin. The composition also possesses cleansing property
without causing dryness to the skin thus, providing better patient
compliance. The topical compositions of the present application are
topical wash compositions.
SUMMARY OF THE INVENTION
[0015] An aspect of the present application relates to a
retinoid-containing topical composition.
[0016] Another aspect of the present application relates to a
topical composition comprising: a) a retinoid compound; b) at least
one foaming agent; c) at least one anti-irritant; and d) one or
more dermatologically acceptable excipient(s).
[0017] Another aspect of the present application relates to a
topical composition comprising: a) tazarotene; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients.
[0018] Another aspect of the present application relates to a
topical composition comprising a) tazarotene; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients; wherein said composition is
applied to the affected area of skin and rinsed off within about 15
minutes; and provides an effective skin deposition of retinoid
compound(s) with less irritation.
[0019] Yet another aspect of the present application relates to a
method of administering a retinoid-containing topical composition
for the treatment of skin disorders such as acne, rosacea,
psoriasis, atopic dermatitis and the like.
[0020] Yet another aspect of the present application relates to a
method of administering a tazarotene containing topical composition
for the treatment of skin disorders such as acne, rosacea,
psoriasis, atopic dermatitis and the like.
[0021] In another aspect, the topical compositions of the present
application are topical wash compositions.
BRIEF DESCRIPTION OF THE DRAWING
[0022] FIG. 1 is a graph showing the effect of number of washes on
cumulative tazarotene deposition in rat skin.
[0023] FIG. 2 is a graph showing the percentage of skin retention
of tazarotene in neonatal minipigs skin.
[0024] FIG. 3 is a graph showing the percentage of skin retention
of tazarotenic acid in neonatal minipigs skin.
[0025] FIGS. 4A-C show the structures of related substances of
tazarotene. FIG. 4A shows Formula III--Methyl
6-[(4,4-dimethyl-3,4-dihydro-2Hthiochromen-6-yl) ethynyl]
nicotinate (Impurity A). FIG. 4B shows Formula IV--Ethyl
6-[(4,4-dimethyl-1-oxido-3,4-dihydro-2H-thiochromen-6-yl) ethynyl]
nicotinate (Impurity B). FIG. 4C shows
6-[(4,4-dimethyl-3,4-dihydro-2H-thiochromen-6-yl)ethynyl] nicotinic
acid (Impurity C).
DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0026] The terms "topical composition," "topical formulation,"
"topical wash composition," or such variants are used
interchangeably in the present application to denote the
composition comprising retinoid compound, especially tazarotene
meant for topical application. In some embodiments, as described in
detail below, the topical composition may tend to form foam at
application site by manual act such as rubbing or massaging, or
applying physical pressure or mechanical device assistance.
[0027] The term "topical wash," as used herein, refers to a
composition having liquid to a gel-like consistency. This term may
be interchangeably used with "skin cleansing composition", "face
wash composition" or "body wash composition", that are useful for
cleansing or rinsing the skin (face, hair or body) for the
treatment of affected skin regions.
[0028] The term "pH balanced", as used herein, refers to a
composition having pH from about 4 to about 7.
[0029] The terms "applying," "administering," or "administration,"
as used herein, refer to topical application of a
retinoid-containing topical composition to affected and adjoining
areas of skin by spreading or gentle rubbing or massaging. The
composition is rinsed off immediately after application without
allowing an extended contact after application.
[0030] The terms "retinoid compound" or "retinoid," as used herein,
refer to any naturally occurring or synthetic derivatives, selected
from tretinoin, tazarotene, tazarotenic acid, adapalene,
isotretinoin, and acitretin. The above active agent may be
administered in the form of its pharmaceutically acceptable salts,
esters, isomers, enantiomers, active metabolites, and/or prodrugs
thereof as well.
[0031] The term "skin disorder(s)," as used herein, refers to any
inflammatory skin disorder selected from acne vulgaris, psoriasis,
rosacea, atopic dermatitis, skin wrinkles, facial mottle,
hyperpigmentation, hypopigmentation, photoaging, papule, pustule,
nodulocystic acne lesion (both inflamed and non-inflamed), and
lentigo.
[0032] As used herein, the term "about," when referring to a value,
or to an amount of mass, weight, time, volume, concentration or
percentage, is meant to encompass variations of, in some aspects,
.+-.20%, in some aspects, .+-.10%, in some aspects, .+-.5%, in some
aspects, .+-.1%, in some aspects .+-.0.5%, and in some aspects,
.+-.0.1% of the specified amount, as such variations are
appropriate to perform the disclosed method.
[0033] The term "aqueous based composition," as used herein, refers
to a composition having a percentage of water in the composition
that is at least about 50% w/w of the final weight of the
composition. In some embodiments, the aqueous-based topical
composition herein refers to a composition comprising at least
about 60% w/w of water based on the final weight of the
composition, or comprising at least about 70% w/w of water based on
the final weight of the composition, or comprising at least about
80% w/w of water based on the final weight of the composition. The
aqueous-based retinoid-containing topical composition provides a
natural feel, non-greasy, no dryness and less irritation to the
skin.
[0034] The terms "active," "active agent," or "active substance,"
as used herein, refer primarily to retinoid compounds. In some
aspects, these terms refer to an active agent other than a retinoid
compound selected from group comprising of: anti-bacterial,
corticosteroids, antimicrobials, anti-leprosy drugs,
immunomodulators, anti-inflammatory agents and/or combination
thereof. In a specific aspect, the one or more active agent(s) are
selected from betamethasone, halobetasol, clobetasol, clofazimine,
azelaic acid, dapsone or combination thereof.
[0035] An aspect of the present application relates to a topical
composition comprising: a) a retinoid compound; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipient(s).
[0036] An aspect of the present application relates to a topical
composition comprising a) a retinoid compound; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients; wherein said composition is
applied to the affected area of skin and rinsed off within about 15
minutes; and provides effective skin deposition of retinoid
compound(s) with less irritation than known retinoid
treatments.
[0037] In another aspect, the topical compositions of the present
application are topical wash compositions.
[0038] In an aspect, the present application relates to a method of
administering retinoid containing topical composition comprising
spreading, gentle rubbing or massaging, and allowing the
composition to remain in the affected area for a minimum period of
time from about 0 seconds to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15 minutes, and rinsing off from the
affected area of skin. Said minimum period of time is less than
about 15 minutes, or less than about 10 minutes, or less than about
5 minutes.
[0039] In one aspect of the present application, the retinoid
compound is selected from tretinoin, tazarotene, tazarotenic acid,
adapalene, isotretinoin or acitretin.
[0040] In another aspect of the present application, the retinoid
compound is a mixture of any of the above-identified compounds.
[0041] In another aspect of the present application, the retinoid
compound is selected from tazarotenic acid, tazarotene or
tretinoin.
[0042] In another aspect of the present application, the retinoid
compound is tazarotene.
[0043] In another aspect of the present application, the
retinoid-containing topical composition is foamable.
[0044] In another aspect of the present application, the retinoid
compound is micronized.
[0045] In another aspect of the present application, the retinoid
compound is in a suspended form in the topical composition.
[0046] In another aspect of the present application, the retinoid
compound is solubilized in a topical composition.
[0047] Another aspect of the present application relates to a
topical composition comprising: a) a retinoid compound; b) at least
one foaming agent; c) at least one anti-irritant; and d) one or
more dermatologically acceptable excipients, wherein the at least
one active agent is other than retinoid compound(s).
[0048] Another aspect of the present application relates to an
aqueous-based topical composition comprising: a) a retinoid
compound; b) at least one foaming agent; c) at least one
anti-irritant; and d) one or more dermatologically acceptable
excipients, wherein the topical composition contains at least about
50, 55, 60, 65, 70, 75, or 80% w/w of water based on the total
weight of the composition.
[0049] Another aspect of the present application relates to a
retinoid-containing topical composition comprising a foaming agent
in the range from about 0.01% w/w to about 10% w/w of the total
weight of the composition. In some embodiments, present application
relates to a retinoid-containing topical composition comprising a
foaming agent at least about 0.01, 0.1, 1.0, 2.0, 3.0, 4.0, 5.0,
6.0, 7.0, 8.0, 9.0, or 10% w/w of total weight of the
composition.
[0050] In an aspect of the present application, the foaming agent
is selected from anionic, cationic, nonionic and amphoteric
surfactants.
[0051] An aspect of the present application relates to a
retinoid-containing topical composition comprising one or more
dermatologically acceptable excipients selected from stabilizers,
fatty alcohols, emollients, fatty acid esters, polymers, chelating
agents, alpha hydroxyl acids, anti-irritants, moisturizing agents,
gelling agents, foaming agents, preservatives, colorants,
antioxidants and pH adjusting agents.
[0052] In an aspect, the present application relates to a
retinoid-containing topical composition which is pH balanced.
[0053] In an aspect, the viscosities of retinoid-containing topical
composition comprising retinoid, frequently vary in from about 100
cps to about 1,00,000 cps, or from about 1000 cps to about 80,000
cps, or from about 1000 cps to about 50,000 cps, when measured by
Brookfield DV-II pro Viscometer with low viscosity spindle no. 4 at
20 rpm, and the another range of viscosity is from about 40,000 cps
to about 1,00,000 cps when measured by Brookfield DV-II pro
Viscometer with low viscosity spindle no. 4 at 5 rpm.
[0054] An aspect of the present application relates to a topical
composition comprising: a) a retinoid compound; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said at least one
anti-irritant is polyhydroxy acid or tocofersolan.
[0055] An aspect of the present application relates to the use of a
polyhydroxy acid in the retinoid-containing topical composition, as
an anti-irritant. The polyhydroxy acid is present in the range from
about 0.01% w/w to about 0.1, 1, 2, or 3% w/w, or from about 0.01,
0.1, 1, or 2% w/w to about 3% w/w, of the total weight of the
composition and is selected from the groups consisting of: gluconic
acid lactone and aldonic acid lactones such as allonolactone,
altronolactone, gluconolactone, mannolactone, gulonolactone,
idonolactone, galactonolactone, and talonolactone.
[0056] An aspect of the present application relates to using of the
combination of anti-irritants in the retinoid-containing topical
composition comprising gluconolactone and tocofersolan.
[0057] Another aspect of the present application relates to a
method of administering the retinoid-containing topical composition
to a patient comprising: a) shaking the composition; b) topically
applying the composition to the affected area of the skin for a
period of about 0 seconds to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15 minutes; and c) rinsing off said
composition from the affected area with water or suitable solvent,
wherein said method deposits retinoid in the affected area of the
skin. Said minimum period of time is less than about 15 minutes, or
less than about 10 minutes, or less than about 5 minutes.
[0058] In an aspect, the present application relates to
administering retinoid containing topical composition to the
affected areas of a patient including, but not limited to, face,
neck, upper chest, back, or any areas of the skin with the densest
population of sebaceous follicles.
[0059] In an aspect, the present application relates to a method of
treating skin disorders using retinoid-containing topical
composition.
[0060] Another aspect of the present application relates to a
method of treating skin disorders by administering a topical
composition comprising: a) a retinoid compound; b) at least one
foaming agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients.
[0061] In an aspect of the present application, the skin disorder
is selected from acne, rosacea, psoriasis, atopic dermatitis, skin
wrinkles, facial mottle, hyperpigmentation, hypopigmentation, photo
aging papule, pustule, nodulocystic acne lesion (both inflamed and
non-inflamed) and lentigo.
[0062] Another aspect of the present application relates to a
method of treating skin disorders by administering a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein the skin disorder
is selected from acne, rosacea, psoriasis, atopic dermatitis, skin
wrinkles, facial mottle, hyperpigmentation, hypopigmentation, photo
aging papule, pustule, nodulocystic acne lesion (both inflamed and
non-inflamed) and lentigo.
[0063] In a specific aspect, the present application relates to a
method of treating acne by administering a topical composition
comprising: a) tazarotene; b) at least one foaming agent; c) at
least one anti-irritant; and d) one or more dermatologically
acceptable excipients, wherein said composition is applied to the
affected area of the skin and rinsed off within about 15 minutes;
and provides an effective skin deposition of tazarotene with less
irritation.
[0064] In a specific aspect, the present application relates to a
method of treating psoriasis by administering a topical composition
comprising: a) tazarotene; b) at least one foaming agent; c) at
least one anti-irritant; and d) one or more dermatologically
acceptable excipients, wherein said composition is applied to the
affected area of skin and rinsed off within about 15 minutes; and
provides an effective skin deposition of tazarotene with less
irritation.
[0065] In an aspect, the present application relates to an
aqueous-based topical composition comprising: a) a retinoid
compound; b) at least one foaming agent; c) at least one
anti-irritant; and d) one or more dermatologically acceptable
agent(s), wherein said retinoid compound is selected from
tazarotene, tretinoin, and adapalene.
[0066] In an aspect, the present application relates to an
aqueous-based topical composition comprising: a) a retinoid
compound; b) at least one foaming agent selected from disodium
laureth sulfosuccinate, cocobetaine, sodium lauryl sarcosinate, and
sodium lauryl sulfate; c) at least one anti-irritant is selected
from polyhydroxy acids; and d) one or more dermatologically
acceptable excipients selected from emollients, antioxidants,
solubilizers, viscosity modifiers, stabilizers, pH adjusting
agents, preservatives, fatty alcohols, fatty acid esters and
polymers, and moisturizers, wherein said composition comprises at
least about 60% w/w water based on the final weight of the
composition.
[0067] In an aspect, the present application relates to an
aqueous-based topical composition comprising: a) from about 0.01%
w/w to about 1% w/w of tazarotene or pharmaceutically acceptable
salt, esters thereof; b) from about 0.1% w/w to about 7% w/w of
foaming agents selected from disodium laureth sulfosuccinate,
cocobetaine, sodium lauryl sarcosinate, and sodium lauryl sulfate,
or mixtures thereof; c) from about 0.01% w/w to about 3% w/w of at
least one anti-irritant selected from polyhydroxy acids and
tocofersolan, or mixtures thereof; and d) one or more
dermatologically acceptable excipients selected from emollients,
antioxidants, stabilizers, pH adjusting agents, preservatives,
fatty alcohols, fatty acid esters and polymers, and moisturizers,
wherein said composition comprises at least about 60% w/w water
based on the final weight of the composition.
[0068] In an aspect, the retinoid-containing topical composition of
the present application relates to a skin-cleansing composition to
wash off debris, oily substances, sebum, and dead cells from the
affected area of the skin, and the retinoid-containing topical
composition can be applied on the affected area of skin and rinsed
off within from about 0 seconds to about 15 minutes, and said
composition comprises a) one or more retinoid(s); b) at least one
anti-irritant; and c) one or more dermatologically acceptable
excipients; wherein the composition provides therapeutically
effective amount of retinoid retention in the skin with less
irritation.
[0069] In another aspect, the retinoid-containing topical
composition of the present application relates to a skin-cleansing
composition to wash off debris, oily substances, sebum, and dead
cells from the affected area of the skin, and the
retinoid-containing topical composition can be applied on the
affected area of skin and rinsed off within from about 0 seconds to
about 15 minutes, and said composition comprises a) tazarotene; b)
at least one anti-irritant; and c) one or more dermatologically
acceptable excipients; wherein the composition provides
therapeutically effective amount of retinoid retention in the skin
with less irritation.
[0070] In an aspect, the topical composition of the present
application comprises: a) tazarotene; b) at least one
anti-irritant; and c) one or more dermatologically acceptable
excipients; wherein said composition is rinsed off within from
about 0 seconds to about 15 minutes; further providing skin
cleansing effect, by washing off debris, oily substances, sebum,
and dead cells from the affected area of the skin, and retention of
therapeutically effective amount of retinoid in the skin with less
irritation.
[0071] In some embodiments, the retinoid-containing topical
composition of the present application has more skin affinity
thereby exhibiting more deposition of retinoid(s) in the skin.
Additionally or alternatively, in some embodiments, the retinoid
compound(s) of the present application is suspended in the
composition, wherein the composition is oil-in-water or
water-in-oil emulsion.
[0072] In one aspect, the retinoid compound(s) in the topical
composition are deposited and entrapped in the pores of the skin
upon application of the topical composition. In another aspect,
these deposited retinoid compounds are not washed off by the
subsequent washes, and tend to release the drug even after
washing.
[0073] An aspect of the present application relates to a
retinoid-containing topical composition comprising water from about
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% w/w to about
95% w/w based on the total weight of the composition. Another
aspect of the present application relates to a retinoid-containing
topical composition comprising water from about 30% w/w to about
35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% w/w based on the
total weight of the composition.
[0074] Another aspect of the present application relates to a
retinoid-containing topical composition comprising water from about
50% w/w to about 90% w/w based on the total weight of the
composition.
[0075] In certain embodiments, particle size of the retinoid
compound(s) is one of the critical aspects of the present
application. Lesser particle size of the retinoid compound(s) tends
to show more skin deposition/retention. However, the extent of
deposition of retinoid compound(s) also depends on the nature of
the composition.
[0076] The cleansing effect of a retinoid-containing topical
composition is optimized. If cleansing effect of the
retinoid-containing topical composition is high, the drug
deposition could to be low due to dislodging of previously
deposited drug. In embodiments described in the present
application, the drug deposition was found to increase linearly
with the increasing number of washes, whereas in some compositions
the initial deposition of drug decreased continuously with
increasing number of washes. It has been found that the net
deposition of drug in the skin is a function of cleansing effect of
the composition that is optimized to maintain the effective level
of the drug in patient skin.
[0077] The skin affinity exhibited by the composition establishes
that the topical composition of the present application deposits
retinoid compound in the skin regardless of its particle size.
[0078] An aspect of the present application relates to a
retinoid-containing topical composition comprising one or more
dermatologically acceptable excipients selected from stabilizers,
solubilizers, solvents, anti-irritants, fatty alcohols, emollients,
fatty acid esters, polymers, chelating agents, alpha hydroxyl
acids, polyhydroxy acids, moisturizing agents, gelling agents,
foaming agents, preservatives, colorants, antioxidants and pH
adjusting agents.
[0079] In an aspect, a retinoid containing topical composition of
the present application may be in the form of lotion, gel, cream,
suspension, foam, soap or spray.
[0080] In an aspect, the retinoid containing topical composition of
the present application may be in the form of a lotion.
[0081] According to one or more of the embodiments disclosed
herein, the retinoid compound(s) are used in the present
application from about 0.001% w/w to about 0.01, 0.1, 1, 2, 3, 4,
or 5% w/w, from about 0.001, 0.01, 0.1, 1, 2, 3, or 4% w/w to about
5% w/w, based on total weight of the composition. In an aspect, the
present application comprises retinoid compound(s) from about 0.01%
w/w to about 0.1% w/w based of total weight of the composition. In
an aspect, the present application comprises retinoid compound(s)
at least about 0.1% w/w based of total weight of the
composition.
[0082] The topical retinoid compositions available in the market
are generally applied once daily before bedtime and these
compositions are left on the skin for a long period of time that
causes significant irritation to the patient's skin. Due to the
chemical nature of retinoid compounds, topical composition
containing a retinoid compound tends to show skin-irritation, and
it is well documented in the state-of-art, and also it has been
observed that skin-irritation caused by retinoid compounds is
directly correlating with their efficacy. Lesser concentration of
retinoid compound(s) shows lesser efficacy and lesser irritation to
skin. Hence, the present retinoid-containing topical composition is
developed in such a way that it enhances skin deposition of
retinoid compound(s) to provide required efficacy and less
irritation. These compositions are completely washable immediately
after application so that it provides better patient
compliance.
[0083] Anti-irritants are often interchangeably used with
humectants/moisturizers. These excipients tend to have soothing
effect on skin dryness caused by foaming agents. The humectant(s)
and moisturizers are selected from, but not limited to, urea,
glycerin polyhydroxy acids, and ammonium lactate. In certain
embodiment disclosed herein, the polyhydroxy acid (PHA) of the
topical composition is one of the critical dermatological
excipients. These PHAs are alpha hydroxyl acids with multiple
hydroxyl groups and act as moisturizers and anti-irritants. The PHA
is selected from gluconic acid lactones and aldonic acid lactones
such as allonolactone, altronolactone, gluconolactone,
mannolactone, gulonolactone, idonolactone, galactonolactone, and
talonolactone, PHA is glucono delta-lactone (gluconolactone).
Gluconolactone is naturally occurring and used in cosmetic
compositions as moisturizer, and humectant. PHA is used in the
present composition in the range from about 0.01, 0.1, 1, or 2% w/w
to about 3% w/w, from about 0.01% w/w to about 0.1, 1, 2, or 3%
w/w, or less than 3% w/w, of total weight of the composition.
[0084] U.S. Pat. Nos. 6,036,963 and 5,654,340 disclose
glucanolactone as a skin wrinkle treatment agent and an
anti-irritant, however these documents do not disclose
glucanolactone in the range of about 0.01 to about 3% of the total
weight of the composition. Particularly US '963 document discloses
at least 3%-8% of glucanolactone as anti-irritant. In the present
application, glucanolactone, alone or in combination with
tocofersolan, exhibits potent anti-irritant property. Tocofersolan
is a polyethylene glycol derivative of .alpha.-tocopherol and is
water soluble. Tocofersolan is used as Vitamin E supplement and
antioxidant in pharmaceutical applications. The percentage weight
ratio of glucanolactone to tocofersolan ranges from 0.001:1 to
1:0.001 based on total weight of the composition, or from 0.1:1 to
1:0.1 based on total weight of the composition. In an aspect, the
percentage weight ratio of glucanolactone to tocofersolan is 1:2
based on total weight of the composition.
[0085] In certain embodiments, foaming agents are important
components of retinoid-containing topical compositions, and render
cleansing property to topical compositions. These foaming agents
can be used alone or in combination thereof. Often, the terms
foaming agent and/or surfactant and/or emulsifying agent are used
interchangeably and are generally described based on
hydrophilic/lipophilic balance (HLB). The HLB scale ranges from 1
(totally lipophilic) to 20 (totally hydrophilic) and is well known
in the art; however this scale is not limited by HLB values, for
example, sodium lauryl sulfate has a HLB value of 40. In the
present application, the term "foaming agent" is commonly used to
encompass all of them as described above and interchangeably used
with "surfactant".
[0086] In some embodiments, the foaming agent(s) used in the
present application may be amphiphilic or hydrophilic substances or
surfactants. In an aspect, foaming agent(s) used in the present
application are selected from, but not limited to, sodium lauryl
sulfate, ammonium lauryl sulfate, dioctyl sodium sulfosuccinate,
sodium dodecyl benzenesulfonate, sodium dodecyl sulfate, potassium
lauryl sulfate; disodium laureth sulfosuccinate, sodium lauroyl
sarcosinate, glycerides such as PEG-6 caprylic/capric glycerides,
betaines such as cocamidopropyl betaine; ethoxylates such as PEG-10
soya sterol, amides such as cocamide DEA, myristamide DEA, or
PEG-20 methyl glucose ether disteartate and ethers, sodium myreth
sulfate, sodium stearate, stearyl alcohol, cetyl alcohol, oleyl
alcohol, cetostearyl alcohol, poloxamer, polysorbate, sorbitan
monostearate, sorbitan tristearate. Other suitable foaming agents
additionally or alternatively include, but are not limited to,
hydrophilic surfactants such as PEG 400 monooleate, PEG 400
monostearate, potassium oleate, sodium oleate, Polyoxyethylene
sorbitan monolaurate (Tween 20), Polyoxyethylene sorbitan
monolaurate (Tween 21), Polyoxyethylene sorbitan monopalmitate
(Tween 40), Polyoxyethylene sorbitan monostearate (Tween 60),
Polyoxyethylene sorbitan monostearate (Tween 61), Polyoxyethylene
sorbitan tristearate (Tween 65), Polyoxyethylene sorbitan
monooleate (Tween 80), Polyoxyethylene sorbitan monooleate (Tween
81), Polyoxyethylene sorbitan trioleate (Tween 85), cocabetaine,
ammonium laureth sulfate and sodium lauryl sulfate or one or more
foaming agents selected from detergents, soaps which tend to foam
upon contact with water.
[0087] The present application relates to a retinoid-containing
topical composition comprising a foaming agent in the range from
about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, or 9% w/w to about 10%
w/w, or from about 0.01% w/w to about 0.1, 1, 2, 3, 4, 5, 6, 7, 8,
9, or 10% w/w, based on total weight of the composition or in the
range from about 0.1% w/w to about 7% w/w based on total weight of
the composition. In certain embodiments disclosed herein, the
concentration of foaming agent(s) is one of the critical parts of
the invention, because choice and concentration of foaming agent
influences the cleansing effect of the topical composition. Certain
foaming agents tend to alter the integrity of stratum corneum (SC)
thereby exhibiting dryness and irritation to the skin.
Moisturizer(s)/emollient(s) balance the effect of foaming agents.
For example, in some embodiments, the foaming agent is used from
about 0.1% w/w to about 7% w/w based on total weight of the
composition, and the foaming agent according to the present
application does not cause over dryness to the skin and does not
disturb the integrity of stratum corneum.
[0088] The hydrophilic surfactants of the present application may
be non-ionic, cationic, anionic, amphoteric or zwitterionic.
Examples of suitable surfactants include, but not limited to,
disodium cocoampho diacetate, oxyethylenated glyceryl cocoate (7
EO), PEG-20 hexadecenyl succinate, PEG-15 stearyl ether, Polyoxyl
20 Cetostearyl Ether, Polypropylene Glycol (PPG)-Stearyl Ether such
as PPG-11 Stearyl Ether and PPG-15 Stearyl Ether, Arlamol E,
ricinoleic monoethanolamide monosulfosuccinate salts,
oxyethylenated hydrogenated ricinoleic triglyceride containing 60
ethylene oxide units such as the products sold by BASF under the
trademarks Cremophor.RTM. RH 60 or Cremophor.RTM. RH 40 (polyoxyl
40 hydrogenated castor oil), polymers such as poloxamers, that are
block copolymers of ethylene oxide and propylene oxide, and the
nonsolid fatty substances at room temperature (that is to say, at
temperatures ranging from about 20 to 35.degree. C.) such as sesame
oil, sweet almond oil, apricot stone oil, sunflower oil,
octoxyglyceryl palmitate (or 2-ethylhexyl glyceryl ether
palmitate), octoxyglyceryl behenate (or 2-ethylhexyl glyceryl ether
behenate), dioctyl adipate, and tartrates of branched dialcohols.
Sorbitan fatty acid esters are series of mixtures of partial esters
of sorbitol and its mono- and dianhydrides with fatty acids.
Sorbitan esters include products sold as Arlacel.RTM. 20, Arlacel
40, Arlacel 60, Arlacel 80, Arlacel 83, Arlacel 85, Arlacel 987,
Arlacel C, PEG-6 stearate and glycol stearate and PEG-32 stearate
(Tefose.RTM. 63), and PEG-6 stearate and PEG-32 stearate
(Tefose.RTM. 1500), and any mixtures thereof. Polyethylene glycol
ethers of stearic acid are among another group of emulsifiers that
can be used in the emulsions. Examples of polyethylene glycol
ethers of stearic acid include steareth-2, steareth-4, steareth-6,
steareth-7, steareth-10, steareth-11, steareth-13, steareth-15,
steareth-20, polyethylene glycol ethers of stearyl alcohol
(steareth 21), and any mixtures thereof. Other emulsifying agents
include sodium lauryl sulphate, cetyl trialkyl ammonium bromide,
polyoxyethylene sorbitan fatty acid esters, and any mixtures
thereof.
[0089] Nonionic surfactants include those that can be broadly
defined as condensation products of long chain alcohols, e.g.,
C8-30 alcohols, with sugar or starch polymers, i.e., glycosides.
Various sugars include, but not limited to, glucose, fructose,
mannose, and galactose, and various long chain alcohols include,
but not limited to, decyl alcohol, cetyl alcohol, stearyl alcohol,
lauryl alcohol, myristyl alcohol, oleyl alcohol, and the like.
[0090] Other useful nonionic surfactants include condensation
products of alkylene oxides with fatty acids, such as alkylene
oxide esters of fatty acids. Other nonionic surfactants are the
condensation products of alkylene oxides with 2 moles of fatty
acids, such as alkylene oxide diesters of fatty acids.
[0091] Examples of amphoteric and zwitterionic surfactants include
those that are broadly described as derivatives of aliphatic
secondary and tertiary amines in which the aliphatic radical can be
straight or branched chain, wherein one of the aliphatic
substituents contains from about 8 to about 22 carbon atoms, and
one contains an anionic water solubilizing group, e.g., carboxy,
sulfonate, sulfate, phosphate, or phosphonate. In an aspect,
surfactants include alkylimino acetates, iminodialkanoates and
aminoalkanoates, and, imidazolinium and ammonium derivatives. Other
suitable amphoteric and zwitterionic surfactants include betaines,
sultaines, hydroxysultaines, alkyl sarcosinates, and alkanoyl
sarcosinates.
[0092] Topical composition of the present application may comprise
one or more solvents that include polyols such as glycerol
(glycerin), propylene glycol, hexylene glycol, diethylene glycol,
propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,
terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene
glycol, other glycols, sulfoxides such as dimethylsulfoxide (DMSO),
dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,
monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide
units), azone (1-dodecylazacycloheptan-2-one),
2-(n-nonyl)-1,3-dioxolane, esters such as isopropyl
myristate/palmitate, ethyl acetate, butyl acetate, methyl
proprionate, capric/caprylic triglycerides, octylmyristate,
dodecyl-myristate; fatty alcohol/acids or its esters such as olelyl
alcohol, cetyl alcohol, myristyl alcohol, stearyl alcohol, lauryl
alcohol, lauric acid, lauryl lactate ketones; amides such as
acetamide, oleates such as triolein; various alkanoic acids such as
caprylic acid; lactam compounds such as azone; alkanols such as
ethanol; dialkylamino acetates, and admixtures thereof.
[0093] In an aspect, topical composition of the present application
comprises retinoid compound(s) in solubilized form, wherein the
retinoid compound(s) is solubilized in one or more solvents as
mentioned above.
[0094] In an aspect, the topical composition of the present
application is foamable. Foamability of the composition is known as
foaming ability (i.e.,) tendency to produce foam of the topical
composition required for cleansing dirt or oil substance or sebum
in the skin, that provides comfortable foaming sensation during
washing, and nice touch during rinsing or after drying, in contrast
to detergents for industrial use.
[0095] In some embodiments, the topical compositions of the present
application are capable of forming a foam by applying manual
pressure such as rubbing the composition at application site of the
skin or massaging the composition at application site.
[0096] In some embodiments, the topical compositions of the present
application comprises one or more foaming agents having HLB value
which provides foam upon rubbing at application site, for example
HLB more than about 10.
[0097] The retinoid-containing topical composition of the present
application may comprise one or more thickeners selected from, but
not limited to, carbomers, polyvinyl pyrrolidone, locust gum,
polyvinyl alcohol, cross-linked polyacrylate polymer, guar gum,
locust bean gum, polysaccharides, and cellulose polymers such as
carboxymethyl cellulose, methocel (HPMC), hydroxyethyl cellulose,
hydroxypropylcellulose, and mixtures thereof.
[0098] The retinoid-containing topical composition of the present
application may comprise one or more pH adjusting agents, selected
from, but not limited to, calcium hydroxide, sodium hydroxide,
potassium hydroxide, and amines such as triethanolamine. In an
embodiment, triethanolamine (also known as trolamine) is a
pH-adjusting agent.
[0099] The term "emollients" are used to denote the substances that
soften and soothe the skin. They are used to correct dryness and
scaling of the skin. Retinoid-containing topical composition of the
present application may comprise one or more emollients selected
from, but not limited to, oils of natural origin such as almond
oil, coconut oil, olive oil, palm oil, peanut oil and the like,
fatty acids such as lauric acid, myristic acid, palmitic acid, and
stearic acid, monohydric alcohol esters of the fatty acids such as
ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl
myristate, isopropyl myristate, ethyl palmitate, isopropyl
palmitate, methyl palmitate, methyl stearate, ethyl stearate,
isopropyl stearate, butyl stearate, isobutyl stearate, amyl
stearate, and isoamyl stearate, glycols such as ethylene glycol,
diethylene glycol, polyethylene glycol, and propylene glycol,
branched aliphatic alcohols such as lauryl alcohol, myristyl
alcohol, and stearyl alcohol, and mixture of fatty alcohols
comprising cetyl and stearyl alcohols such as cetearyl alcohol,
mineral oil, and any combinations thereof.
[0100] The term "antioxidants" is used to denote the substances
which inhibit oxidation or suppress reactions promoted by oxygen or
peroxides. Antioxidants, especially lipid-soluble antioxidants, can
be absorbed into the cellular membrane to neutralize oxygen
radicals and thereby protect the membrane. The retinoid-containing
topical composition of the present application may comprise one or
more antioxdants, selected from, but not limited to, ascorbic acid
(vitamin C), glutathione, lipoic acid, uric acid, carotenes,
.alpha.-tocopherol (vitamin E), tocofersolan, ubiquinol, butylated
hydroxyanisole, butylated hydroxytoluene, sodium benzoate, propyl
gallate (PG, E310), and tertiary-butylhydroquinone. The amounts of
antioxidants may be from about 0.01% to about 10%, of the total
weight of the composition.
[0101] The term "preservative" refers to a natural or a synthetic
chemical that is added to products to prevent decomposition by
microbial growth or by undesirable chemical changes. Preservatives
can desirably be incorporated into a composition for the protection
against the growth of potentially harmful microorganisms. While
microorganisms tend to grow in an aqueous phase, these can also
reside in a hydrophobic or an oil phase. The retinoid-containing
topical composition of the present application may comprise one or
more preservatives, selected from, but not limited to,
methylparaben, propylparaben, benzyl alcohol, chlorocresol,
benzalkonium chloride, cetrimonium chloride, sodium edetate, boric
acid, sorbic acid, potassium sorbate, sodium benzoate, methylchloro
isothiazolinone, methyl isothiazolinone, diazolidinyl urea,
Imidazolidinyl urea, and any mixtures thereof. The amount of
preservative may be from about 0.25% to about 2.5, 5, 10, 15, 20 or
25% w/w of the total weight of the composition.
[0102] In an aspect, retinoid-containing topical composition
optionally comprises a chelating agent. The chelating agents are
selected from, but not limited to, ethylenediamine tetraacetic acid
(EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA,
H-EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium
phosphate, diammonium citrate, galactaric acid, galacturonic acid,
gluconic acid, glucuronic acid, humic acid, cyclodextrin, potassium
citrate, the potassium salt of ethylenediamine-tetra (methylene
phosphonic acid) (EDTMP), sodium citrate, sodium EDTMP, and the
like, and any mixtures thereof.
[0103] Another aspect of the present application relates to an
aqueous-based retinoid containing topical composition comprising:
a) tazarotene; b) at least one foaming agent; c) at least one
anti-irritant; and d) one or more dermatologically acceptable
excipients, wherein the topical composition contains at least about
60% w/w of water based on the total weight of the composition.
[0104] Another aspect of the present application relates to a
retinoid containing topical composition comprising: a) tazarotene;
b) at least one foaming agent; c) at least one anti-irritant; and
d) one or more dermatologically acceptable excipients, wherein said
at least one anti-irritant is polyhydroxy acid or tocofersolan.
[0105] Another aspect of the present application relates to a
retinoid containing topical composition comprising: a) tazarotene;
b) at least one foaming agent; c) at least one anti-irritant; and
d) one or more dermatologically acceptable excipients, wherein said
at least one anti-irritant is gluconolactone and tocofersolan.
[0106] In an aspect, the present application relates to an
aqueous-based retinoid-containing topical composition comprising:
a) from about 0.01% w/w to about 1% w/w of tazarotene or
pharmaceutically acceptable salts or esters thereof; b) from about
0.1% w/w to about 7% w/w of foaming agents selected from disodium
laureth sulfosuccinate, cocobetaine, sodium lauryl sarcosinate, and
sodium lauryl sulfate, or mixtures thereof; c) from about 0.01% w/w
to about 3% w/w of a polyhydroxy acid as an anti-irritant; and d)
one or more dermatologically acceptable excipients selected from
emollients, antioxidants, solubilizers, viscosity modifiers,
stabilizers, pH adjusting agents, preservatives, fatty alcohols,
fatty acid esters and polymers, and moisturizers, wherein said
composition comprises at least about 60% w/w water based on the
final weight of the composition.
[0107] In an aspect, retinoid-containing topical composition of the
present application provides an effective amount of tazarotene to
the skin layer, wherein said topical composition provides 0.01
.mu.g to 10 .mu.g of tazarotene concentration in the skin layer
that comprises epidermis and/or dermis. The retinoid-containing
topical composition of the present application provides more
concentration of tazarotene in the epidermis layer than the dermis
layer.
[0108] In certain embodiments, the topical composition of the
present application comprises tazarotene that is deposited in the
affected area of the skin at a concentration of more than 0.1% of
TAZORAC topical gel.
[0109] In some embodiments, the topical composition of present
application comprises tazarotene and/or pharmaceutically acceptable
salts thereof, wherein tazarotene is suspended in the composition.
In an aspect of the present application, tazarotene is in
micronized form. In another aspect, the particle size of micronized
tazarotene has D90 less than about 70 .mu.m, or D90 is in the range
from about 5 .mu.m to about 60 .mu.m, or D90 is about 10 .mu.m. In
a further aspect, the particle size of micronized tazarotene has
D50 less than about 500 .mu.m, or D50 is in the range from about 50
.mu.m to about 100 .mu.m, or D50 is about 10 .mu.m.
[0110] In an aspect, the topical composition of the present
application comprises tazarotene and/or pharmaceutically acceptable
salts thereof, wherein tazarotene is in the suspended form. In a
specific aspect, said composition is pH balanced and stable. In
another aspect, tazarotene tends to dissolve at a pH below 3 which
causes degradation.
[0111] In an aspect, the present application relates to a stable
retinoid-containing topical composition. The term "stable" as used
herein refers to physical stability and/or chemical stability of
the active agent in the composition, wherein changes in the drug
assay values and/or impurities content are less than about 5%,
during storage stability study of the composition at 25.degree. C.
and 60% relative humidity (RH), or 30.degree. C. and 65% RH, or
40.degree. C. and 75% RH, for durations such as 3, 6, 12, 18, or 24
months.
[0112] In an aspect, the topical composition comprises tazarotene
and optionally contains one or more of related substances, such as
impurity A (methyl 6-[(4,4-dimethyl-3,4-dihydro-2H
thiochromen-6-yl) ethynyl] nicotinate) in amounts not more than
about 0.1%; impurity B (ethyl
6-[(4,4-dimethyl-1-oxido-3,4-dihydro-2H-thiochromen-6-yl) ethynyl]
nicotinate) in amounts not more than about 2%; impurity C
(6-[(4,4-dimethyl-3,4-dihydro-2H-thiochromen-6-yl)ethynyl]
nicotinic acid) in amounts not more than about 0.1%. The above
impurity limits are expressed as percentages of the label drug
content in the topical composition.
[0113] In an aspect, the present application relates to a method of
treating skin disorders by retinoid-containing topical composition
comprising: a) shaking the composition; b) topically applying the
composition to the affected area of the skin for a period of about
0 seconds to about 15 minute; and c) rinsing-off said composition
from the affected area with water or suitable solvent. In an
aspect, said minimum period of time is from about 30 seconds to
about 10 minutes. In an aspect, said minimum period of time is from
about 30 seconds to about 5 minutes.
[0114] In an aspect, the present application relates to a method of
treating acne in a patient in need thereof, comprising topically
administering retinoid-containing topical composition of the
present application, wherein said composition administers an
effective amount of retinoid compound(s) to the skin.
[0115] In an aspect, the present application relates to a method of
treating acne vulgaris in a patient in need thereof, comprising
topically administering the topical composition comprising: a) from
about 0.01% w/w to about 1% w/w of tazarotene or pharmaceutically
acceptable salts, esters thereof; b) from about 0.1% w/w to about
7% w/w of foaming agents selected from disodium laureth
sulfosuccinate, cocobetaine, sodium lauryl sarcosinate, and sodium
lauryl sulfate, or mixtures thereof; c) from about 0.01% w/w to
about 3% w/w of an anti-irritant selected from polyhydroxy acids;
and d) one or more dermatologically acceptable excipients selected
from emollients, antioxidants, solubilizers, viscosity modifiers,
stabilizers, pH adjusting agents, preservatives, fatty alcohols,
fatty acid esters and polymers, and moisturizers.
[0116] Another aspect of the present application relates to a
process of preparing retinoid-containing topical composition
comprising the steps of: 1) preparing retinoid-containing
dispersion comprising: mixing retinoid compound with foaming agent
and water; 2) preparing an emulsion by mixing aqueous phase and oil
phase under homogenization; 3) preparing the composition by mixing
retinoid-containing dispersion and emulsion together under
homogenization; 4) and adjusting the pH of the retinoid-containing
topical composition using a suitable pH adjusting agent in the
range of about 4 to about 7.
[0117] An aspect of the present application further provides a
process for preparing retinoid-containing topical composition to be
filled into any suitable dispensing device. In an aspect, a process
of preparing retinoid-containing topical composition comprises the
steps of: 1) preparing aqueous phase comprising: mixing: a)
sufficient quantity of water, b) humectant and/or moisturizer, c)
preservative(s) d) foaming agent, and other suitable excipients, at
a desired temperature under homogenization, wherein due care is
taken to avoid foam during homogenization; 2) preparing oil phase
comprising: mixing solvent optionally with emollients, lipid
soluble antioxidants etc. at a desired temperature under
homogenization; 3) preparing emulsion comprising: mixing aqueous
phase of step 1 and oil phase of step 2 at a desired temperature
under homogenization, and optionally adjusting the pH to a desired
level; 4) preparing drug-containing dispersion comprising: mixing
a) retinoid, b) foaming agent, and c) water at a desired
temperature under homogenization; and 5) preparing the composition
by mixing drug dispersion of step 4 and emulsion of step 3 at a
desired temperature under homogenization, and adjusting the pH to a
desired level.
[0118] In one aspect, the topical compositions of the present
application comprises at least one oil phase and one hydrophilic
phase. For example, in some embodiments, the topical composition of
present application is a biphasic composition such as oil-in-water
emulsion, or water-in-oil emulsion, or suspension, or suspension
gel or monophasic composition such as suspension, or suspension
gel.
[0119] In an aspect, the oil phase of the topical composition of
the present application comprises one or more water immiscible
substances that can act as emollient. Suitable water immiscible
substances that can be used in the present application are selected
from, but not limited to, vegetable oils, derivatives of vegetable
oils, medium chain triglycerides (naturally occurring/isolated from
natural source or synthetic), vitamin E or its derivatives, water
immiscible emollient substances, fatty alcohols and the like or
mixtures thereof. The fatty alcohols are selected from, but not
limited to, lauryl alcohol, stearyl alcohol, cetostearyl alcohol,
cetyl alcohol, oleyl alcohol or mixtures thereof. The vegetable
oils are selected from, but limited to, soybean oil, corn oil,
safflower oil, sesame oil, olive oil, castor oil or a mixture
thereof. The medium chain triglycerides are medium chain fatty
acids esterified with glycerides, which are selected from, but not
limited to, capric/caprylic triglycerides.
[0120] In another aspect, the oil phase of the present topical
composition is interchangeably referred to as emollients. In
another aspect, the topical composition of the present application
without the active substance is interchangeably referred to as
emollient base composition or emollient vehicle.
[0121] In an aspect, the oil phase present in the composition of
present application in an amount of about 0% to about 40% based on
the total weight of the composition, or from about 1% to about 30%
based on the total weight of the composition or from about 1% to
about 20% based on the total weight of the composition.
[0122] In an aspect, the hydrophilic phase of the topical
compositions of the present application comprises one or more
excipients selected from water, gelling agent, foaming agent, pH
adjusting agent, humectant, preservatives, antioxidants,
anti-irritants, and the like.
[0123] In another aspect, the hydrophilic phase present in the
composition of present application comprises at least about 60% of
water or at least about 70% of water or at least about 80% of
water.
[0124] The concentration of gelling agent is critical in terms of
flow properties of the composition. Higher concentration of gelling
agent indicates high viscosity and short flow properties of the
composition. In an aspect, the gelling agent used in the present
application is present in the amount of from about 0.01% to about
2%. In another aspect, the gelling agent is present in an amount of
from about 0.1% to about 1%.
[0125] In another aspect, the topical composition of present
application is capable of forming foam.
[0126] In another aspect, the topical composition of present
application is non-sprayable.
[0127] In another aspect, the topical composition of present
application is non-sprayable and pourable liquid topical dosage
form, wherein said composition is in the form of suspension,
emulsion or lotion.
[0128] In another aspect, the topical composition of present
application is propellant free.
[0129] In another aspect, the topical composition of present
application is homogenous suspension or suspension gel or
emulgel.
[0130] In another aspect, the topical composition of present
application comprises substantial amount of tazarotene or its
pharmaceutically acceptable salts or esters thereof, in the
hydrophilic phase. The term "substantial amount" as used herein
denotes at least about 80% of label amount of the active substance
or at least about 90% of label amount of the active substance or at
least about 95% of label amount of the active substance or at least
about 100% of label amount of the active substance. The term
"substantial amount in hydrophilic phase" as denoted in the context
of the present application comprises at least about 80% of label
amount of the active substance suspended in hydrophilic phase of
the topical composition.
[0131] In another aspect, the topical composition of present
application is storage stable. The term "storage stable" as used
herein denotes physical stability of the topical composition at
controlled room temperature without phase separation or particle
ripening i.e. suspended particle aggregation, or sedimentation or
precipitation or change in color or any such physical
attributes.
[0132] In another aspect of the present application, the tazarotene
used in the topical composition of the present application has D90
particle size of not more than about 50 microns, or not more than
about 40 microns, or not more than about 30 microns, or not more
than about 20 microns.
[0133] In another aspect, the oil phase used in the composition of
the present application has D90 globule size of not more than about
50 microns, or not more than about 40 microns, or not more than
about 30 microns, or not more than about 20 microns, or not more
than about 10 microns.
[0134] In another aspect, the topical composition of the present
application is storage stable and does not show any variations in
the oil globule size at least for 3 months at 25.degree. C. or at
least for 6 months at 25.degree. C. or at least for 9 months at
25.degree. C. or at least for 12 months at 25.degree. C. or at
least for 24 months at 25.degree. C.
[0135] In another aspect, the topical composition of the present
application is storage stable and does not show any phase
separation at least for 3 months at 25.degree. C. or at least for 6
months at 25.degree. C. or at least for 9 months at 25.degree. C.
or at least for 12 months at 25.degree. C.
[0136] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) at least one foaming agent;
c) an anti-irritant selected from polyhydroxy acids; and d) one or
more dermatologically acceptable excipients wherein said
composition is homogenous suspension containing tazarotene in
suspended form.
[0137] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said anti-irritant
is selected from polyhydroxy acids in the range of about 0.01% to
about 3% of the total weight of the composition, and said
composition is storage stable.
[0138] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said anti-irritant
is selected from polyhydroxy acids in the range of about 0.01% to
about 3% of the total weight of the composition, and said
composition is storage stable having D90 globule size of oil phase
not more than about 50 microns.
[0139] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said anti-irritant
is selected from polyhydroxy acids in the range of about 0.01% to
about 3% of the total weight of the composition, and said
composition is storage stable having D90 globule size of oil phase
not more than about 50 microns and D90 particle size of said
tazarotene not more than about 50 microns.
[0140] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said anti-irritant
is selected from polyhydroxy acids in the range of about 0.01% to
about 3% of the total weight of the composition, and said
composition is storage stable and pH of said composition is from
about 4 to about 7.
[0141] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) at least one foaming
agent; c) at least one anti-irritant; and d) one or more
dermatologically acceptable excipients, wherein said anti-irritant
is selected from polyhydroxy acids in the range of about 0.01% to
about 3% of the total weight of the composition, and said
composition is storage stable and pH of said composition is from
about 4 to about 7; wherein said tazarotene is suspended in the
composition.
[0142] In another aspect, the oil phase has D90 globule size of not
more than about 50 microns or not more than about 40 microns, or
not more than about 30 microns, or not more than about 20 microns,
or not more than about 10 microns. In some aspects, the oil phase
has D50 globule size of not more than about 30 microns, or not more
than about 20 microns, or not more than about 10 microns or not
more than about 5 microns. In some aspects, the oil phase has D10
globule size of not more than about 10 microns, or not more than
about 5 microns. In yet another aspect, the topical compositions of
the present application are interchangeably referred to as
microemulsion or emulgel or suspension gel or foamable suspension
gel or foaming gel.
[0143] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; c) an anti-irritant
selected from polyhydroxy acids; and d) one or more
dermatologically acceptable excipients; wherein said composition
tends to form foam upon rubbing at application site of the subject
skin.
[0144] In an aspect, the composition is of the present application
is foamable at the application site, upon applying manual act such
as rubbing or massaging, and the foaming tendency of the
composition increases while applying to the wet skin.
[0145] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; and c) one or more
dermatologically acceptable excipients; wherein said composition
tends to form foam upon rubbing at application site of the subject
skin.
[0146] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; and c) one or more
dermatologically acceptable excipients; wherein said tazarotene is
present in suspended form and the D90 particle size of the
tazarotene is not more than about 50 microns or not more than about
40 microns, or not more than about 30 microns, or not more than
about 20 microns.
[0147] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; c) an anti-irritant
selected from polyhydroxy acids; and d) one or more
dermatologically acceptable excipients; wherein said tazarotene is
present in suspended form and the D90 particle size of the
tazarotene is not more than about 50 microns or not more than about
40 microns, or not more than about 30 microns, or not more than
about 20 microns.
[0148] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; c) an anti-irritant
selected from polyhydroxy acids; and d) one or more
dermatologically acceptable excipients; wherein said tazarotene is
present in suspended form and the D90 particle size of the
tazarotene is not more than about 50 microns.
[0149] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; c) an anti-irritant
selected from polyhydroxy acids; and d) one or more
dermatologically acceptable excipients; wherein said tazarotene is
present in suspended form and the D90 particle size of the
tazarotene is not more than about 40 microns.
[0150] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value of more than about 10; c) an anti-irritant
selected from polyhydroxy acids; and d) one or more
dermatologically acceptable excipients; wherein said tazarotene is
present in suspended form and the D90 particle size of the
tazarotene is not more than about 30 microns. C.
[0151] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agent; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipient.
[0152] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipients; wherein said
composition further comprises an anti-irritant selected from
polyhydroxy acid in the range of about 0.1% w/w to about 3% w/w
based on total weight of the composition.
[0153] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipient; wherein said
composition is storage stable.
[0154] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipient; wherein said
composition is storage stable and D90 particle size of tazarotene
is less than about 50 microns.
[0155] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipient; wherein said
composition is storage stable and D90 globule size of oil phase is
less than about 50 microns.
[0156] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipient; wherein said
composition is storage stable and D90 particle size of tazarotene
is less than about 50 microns and D90 globule size of oil phase is
less than about 50 microns, and said composition does not show
change in particle size and/or globule size at least for about 3
months at 25.degree. C. or at least for about 6 months at
25.degree. C. or at least for about 9 months at 25.degree. C. or at
least for about 12 months at 25.degree. C. or at least for about 24
months at 25.degree. C.
[0157] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) one or more foaming
agents; c) an oil phase comprising one or more water immiscible
substances; d) a hydrophilic phase comprising water; and e) one or
more dermatologically acceptable excipients; wherein substantial
amount of said tazarotene is present in a hydrophilic phase and the
D90 particle size of the tazarotene is not more than about 50
microns or not more than about 40 microns, or not more than about
30 microns, or not more than about 20 microns.
[0158] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value more than about 10; c) an anti-irritant selected
from polyhydroxy acids; d) an oil phase comprising one or more
water immiscible substances; e) a hydrophilic phase comprising
water; and f) one or more dermatologically acceptable excipients;
wherein substantial amount of said tazarotene is present in the
hydrophilic phase and the D90 particle size of the tazarotene is
not more than about 50 microns or not more than about 40 microns,
or not more than about 30 microns, or not more than about 20
microns.
[0159] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents;
c) a gelling agent; d) an oil phase; e) a hydrophilic phase
comprising water; and f) one or more dermatologically acceptable
excipients; wherein said composition is a suspension in which
tazarotene is suspended by gelling agent, and the D90 particle size
of the tazarotene is not more than about 50 microns or not more
than about 40 microns, or not more than about 30 microns, or not
more than about 20 microns.
[0160] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents;
c) a gelling agent; d) an oil phase comprising one or more water
immiscible substances; e) a hydrophilic phase comprising water; f)
an anti-irritant selected from polyhydroxy acids; and g) one or
more dermatologically acceptable excipients; wherein said
composition is a suspension in which tazarotene is suspended by
gelling agent, and the D90 particle size of the tazarotene is not
more than about 50 microns or not more than about 40 microns, or
not more than about 30 microns, or not more than about 20
microns.
[0161] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value more than about 10; c) an oil phase comprising one
or more fatty alcohols; c) a hydrophilic phase comprising
substantial amount of tazarotene, an anti-irritant selected from
polyhydroxy acid in the range of about 0.01% to about 3% of the
total weight of the composition, water not less than 50%; wherein
said composition is foamable and propellant free.
[0162] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more foaming agents
having HLB value more than about 10; c) an oil phase comprising one
or more fatty alcohols; c) a hydrophilic phase comprising
substantial amount of tazarotene, an anti-irritant selected from
polyhydroxy acid in the range of about 0.01% to about 3% of the
total weight of the composition, water not less than 50%; wherein
said composition is capable of forming foaming, upon applying at
application site.
[0163] As described above, in some embodiments, the topical
composition of the present application is foamable. In one aspect,
the foaming capacity of compositions of the present application is
from about 5 ml to about 120 ml.
[0164] In an aspect, the foaming capacity of the compositions of
the present application is from about 10 ml to about 100 ml, or
from about 15 ml to about 95 ml, or from about 20 ml to about 90
ml. In some other aspects, the foaming capacity of the topical
compositions of the present application is not less than about 10
ml, and not more than about 50 ml.
[0165] In some embodiments, tazarotene undergoes degradation in the
presence of excipients which causes oxidation, for example alpha
hydroxyl acid, polysorbate, benzyl alcohol, isostearic acid and the
like.
[0166] In an aspect, the topical composition of the present
application is free of alpha or beta hydroxy acids such as lactic
acid, or glycolic acid.
[0167] In an aspect, the topical composition of the present
application is free of lactic acid.
[0168] In an aspect, the topical composition of the present
application is free of glycolic acid.
[0169] In an aspect, the topical composition of the present
application is free of benzyl alcohol.
[0170] In one aspect, the present application relates to a topical
composition comprising tazarotene, wherein said tazarotene is not
in a solubilized form, but in suspended form. Yet the content
uniformity of tazarotene in the dosage form is maintained.
[0171] In an aspect, the topical composition of the present
application comprises: a) tazarotene or its pharmaceutically
acceptable salts or esters thereof; b) one or more anti-irritants
selected from polyhydroxy acid, Vitamin E derivative or mixtures
thereof, in an amount of about 0.1% to about 3%; c) one or more
foaming agents selected from sodium lauryl sulphate, disodium
laureth sulfosuccinate, cocobetaine, sodium lauroyl sarcosinate or
mixtures thereof, in an amount of about 0.1% to about 10%; and d)
one or more pharmaceutically acceptable excipients; wherein said
tazarotene is suspended in the composition and said composition is
in the form of monophasic gel.
[0172] In another aspect, the topical composition of the present
application is in the form of oil-in-water emulsion, comprising: a)
hydrophilic phase comprising i) tazarotene or its pharmaceutically
acceptable salts or esters thereof and ii) a gelling agent; b) an
oil phase comprising one or more water immiscible substances,
selected from fatty alcohols, vegetable oils, medium chain
triglycerides mineral oil or mixtures thereof; c) one or more
foaming agents selected from sodium lauryl sulphate, disodium
laureth sulfosuccinate, cocobetaine, or sodium lauroyl sarcosinate
or mixtures thereof, in an amount of about 0.1% to about 10%; and
d) one or more pharmaceutically acceptable excipients; wherein said
tazarotene is suspended in the hydrophilic phase and said
composition has a pH of about 4 to about 7.
[0173] In an aspect, the topical composition of the present
application is prepared by a process comprising a
pre-neutralization step.
[0174] In another aspect, the present invention relates to a
process of preparing topical composition comprising tazarotene or
its pharmaceutically acceptable salts or esters thereof, wherein
said process comprises steps of: a) preparing an oil phase, b)
preparing a hydrophilic phase, c) preparing the tazarotene phase,
and d) emulsification, wherein said tazarotene phase is added after
emulsification, and said emulsification step further comprises
pre-neutralization step using pH adjusting agent to pH of above
about 5.
[0175] The pre-neutralization step is carried out by the addition
of a pH adjusting agent such as sodium hydroxide, triethanolamine,
citric acid, hydrochloric acid and the like. The pre-neutralization
step is carried out to prevent the solubilization of tazarotene in
the oil phase comprising one or more medium chain triglycerides. In
the lower pH tazarotene tend to solubilize in oil phase, leading to
tazarotene degradation in the solubilized form.
[0176] In another aspect, the topical composition of the present
application is in the form of oil-in-water emulsion, and comprises:
a) hydrophilic phase comprising i) tazarotene or its
pharmaceutically acceptable salts or esters thereof, from about
0.01% to about 0.2%, ii) a gelling agent, and iii) water; b) an oil
phase; c) one or more foaming agent; and d) one or more
pharmaceutically acceptable excipients; wherein said tazarotene is
suspended in hydrophilic phase, and said composition is prepared by
a process comprising pre-neutralization step to prevent
solubilization of tazarotene.
[0177] In an aspect, the present application relates to a process
of preparing topical composition comprising tazarotene or its
pharmaceutically acceptable salts or esters thereof, wherein the
process comprises steps of: a) preparing a hydrophilic phase
comprising water and a gelling agent; b) preparing an oil phase
comprising one or more emollient substances; c) emulsification and
pre-neutralization to adjust the pH from about 4 to about 7; d)
preparing tazarotene phase comprising tazarotene and water; and e)
homogenizing the tazarotene phase with emulsion of step c.
[0178] In one aspect, the pharmacokinetic parameters of
compositions of the present application are compared with
TAZORAC.RTM. cream.
[0179] As used herein, the term "TAZORAC.RTM." refers to any
topical composition comprising tazarotene in the strength of 0.1%,
which are pharmaceutical equivalent, therapeutically equivalent,
bioequivalent as defined by US FDA, and said topical composition
can be in any suitable topical dosage form. TAZORAC.RTM. is a
registered trademark of Allergan Inc. and is available as cream and
gel. For example, TAZORAC.RTM. cream contains tazarotene 0.1% and
the following inactive ingredients: benzyl alcohol 1%, carbomer
1342, carbomer homopolymer type B, edetate disodium, medium chain
triglycerides, mineral oil, purified water, sodium hydroxide,
sodium thiosulfate, and TAZORAC.RTM. gel contains tazarotene 0.1%
and the following inactive ingredients: sorbitan monooleate and
ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene,
carbomer homopolymer type B, edetate disodium, hexylene glycol,
poloxamer 407, polyethylene glycol 400, polysorbate 40, purified
water and tromethamine.
[0180] In one aspect, "tazarotene" is administered as
pharmaceutically acceptable form, including, but not limited to,
tazarotene or its pharmaceutically acceptable salts, esters,
isomers, prodrugs or mixtures thereof. Upon administration
tazarotene provides tazarotenic acid, its active metabolite in the
system.
[0181] In an aspect, the present application relates to a topical
composition comprising tazarotene, wherein said composition
provides systemic exposure of tazarotene and/or tazarotenic acid,
less than or similar as compared to TAZORAC.RTM. cream.
[0182] The term "systemic exposure" as used herein denotes an
amount of tazarotene and/or its active metabolite (tazarotenic
acid) available in the systemic circulation of the subject, pre or
post topical application of composition of the present application
and said systemic exposure of tazarotene and/or tazarotenic acid is
defined in terms of pharmacokinetic parameters such as Area under
curve (AUC.sub.0-12, or AUC.sub.0-24), or maximum plasma
concentration (C.sub.max) or time to reach maximum concentration
(T.sub.max). The subjects for pharmacokinetic study are selected
from healthy human volunteers, or subject with skin disorders such
as psoriasis or acne vulgaris, or a mammalian animal such as rat,
mice and the like. Said pharmacokinetic parameters are expressed as
mean values obtained from subjects using various statistical
methods known, such as natural logarithmic transformation etc. and
the values mentioned herein are statistically significant
p<0.001 or p<0.05 or 90% co-efficient of variation or 90%
confidence interval or 95% confidence interval or 99% confidence
interval.
[0183] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) an anti-irritant; c) a
foaming agent; and d) a pharmaceutically acceptable excipient;
wherein said composition provides systemic exposure of tazarotene
and/or tazarotenic acid, less than or similar as compared to
TAZORAC.RTM..
[0184] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) an anti-irritant; c) a
foaming agent; and d) a pharmaceutically acceptable excipient;
wherein said composition provides systemic exposure of tazarotene
and/or tazarotenic acid, less than or similar as compared to
TAZORAC.RTM. cream.
[0185] In an aspect, the present application relates to a topical
composition comprising: a) tazarotene; b) an anti-irritant selected
from polyhydroxy acids; c) a foaming agent selected from disodium
laureth sulfosuccinate, cocobetaine, sodium lauryl sarcosinate, and
sodium lauryl sulfate; and d) a pharmaceutically acceptable
excipient; wherein said composition provides systemic exposure of
tazarotene and/or tazarotenic acid, less than or similar as
compared to TAZORAC.RTM..
[0186] In another aspect, TAZORAC.RTM. is TAZORAC.RTM. cream.
[0187] In another aspect, TAZORAC.RTM. is TAZORAC.RTM. gel.
[0188] In an aspect, the present application relates to a method of
administering topical composition comprising tazarotene to a
subject once or twice daily.
[0189] The topical treatment with TAZORAC.RTM. involves application
of the product to a subject's affected area as a thin film (2
mg/cm2) once per day, especially in the evening time, for the
treatment of psoriasis or acne vulgaris. The topical compositions
of the present application are applied to the affected area of the
subject and rinsed off immediately or within 5 minutes provides
similar or less systemic exposure of tazarotene and/or tazarotenic
acid as compared to TAZORAC.RTM. cream applied overnight.
[0190] The administration of topical composition of the present
application involves administration of the composition and rinsed
off within 5 minutes from administration, yet the systemic exposure
of tazarotene and/or tazarotenic acid is similar or less than the
TAZORAC.RTM. cream once daily overnight application (12 hours).
[0191] The topical composition of the present application
comprising tazarotene, is intended for administering as washable
composition to a subject and said administration is not left over
for a time period but is rinsed off immediately i.e. within 5
minutes.
[0192] The topical composition of the present application provides
less systemic exposure of tazarotene and/or tazarotenic acid in the
subject's plasma. The minimum contact time application of topical
composition of present application provides tazarotene deposition
at skin layer which provides retinoid activity to elicit
therapeutic effect in the affected area.
[0193] In an aspect, the present application relates to a method of
administering a topical composition of tazarotene to a subject;
wherein said method comprises: spreading, gentle rubbing or
massaging; and allowing the composition to remain in the affected
area for a minimum period of time, wherein said minimum period of
time is less than about 5 minutes; wherein said method provides
systemic exposure of tazarotene and/or tazarotenic acid, less than
or similar as compared to TAZORAC.RTM., for example as compared to
TAZORAC.RTM. cream.
[0194] In another aspect, the minimum period of time is less than
about 4 minutes, or less than about 3 minutes or less than about 2
minutes or less than about 1 minute.
[0195] In an aspect, the topical composition is a topical wash
composition i.e. easily washable composition, and rinsed off within
5 minutes from application site, and provides therapeutically
effective concentration to the skin, and systemic exposure of
tazarotene and/or tazarotenic acid is less or similar as compared
to TAZORAC.RTM. cream. Said topical composition is administered
once or twice daily with minimum contact time of less than about 5
minutes.
[0196] In an aspect, the topical composition of present application
provides less systemic exposure of tazarotene and/or tazarotenic
acid, when administered once daily for 14 days as compared to
TAZORAC.RTM. cream.
[0197] In an aspect, the topical composition of present application
provides similar systemic exposure of tazarotene and/or tazarotenic
acid, when administered twice daily for 14 days as compared to
TAZORAC.RTM. cream.
[0198] The term "about" in the context of pharmacokinetic
parameters is modifying term from the absolute value mentioned over
there. The term "about" in the context of AUC.sub.0-24 is .+-.100
pgh/ml or is .+-.90 pgh/ml or is .+-.80 pgh/ml or is .+-.70 pgh/ml
or is .+-.60 pgh/ml or is .+-.50 pgh/ml or is .+-.40 pgh/ml or is
.+-.30 pgh/ml or is .+-.20 pgh/ml or is .+-.10 pgh/ml. The term
"about" in the context of C.sub.max is .+-.100 pg/ml or is .+-.90
pg/ml or is .+-.80 pg/ml or is .+-.70 pg/ml or is .+-.60 pg/ml or
is .+-.50 pg/ml or is .+-.40 pg/ml or is .+-.30 pg/ml or is .+-.20
pg/ml or is .+-.10 pg/ml.
[0199] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 2550 pgh/ml on
day 1 post treatment, when administered as topical composition
twice daily for 14 days.
[0200] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 1690 pgh/ml on day 1 post
treatment, when administered as topical composition twice daily for
14 days.
[0201] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 3875 pgh/ml on
day 7, when administered as topical composition twice daily for 14
days.
[0202] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 3515 pgh/ml on day 7, when
administered as topical composition twice daily for 14 days.
[0203] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 5410 pgh/ml on
day 14, when administered as topical composition twice daily for 14
days.
[0204] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 4310 pgh/ml on day 14, when
administered as topical composition twice daily for 14 days.
[0205] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 1200 pgh/ml on
day 1 post treatment, when administered as topical composition once
daily for 14 days.
[0206] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 1000 pgh/ml on day 1 post
treatment, when administered as topical composition once daily for
14 days.
[0207] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 1400 pgh/ml on
day 7, when administered as topical composition once daily for 14
days.
[0208] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 1275 pgh/ml on day 7, when
administered as topical composition once daily for 14 days.
[0209] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid less than about 1800 pgh/ml on
day 14, when administered as topical composition once daily for 14
days.
[0210] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
AUC.sub.0-24) of tazarotenic acid about 1515 pgh/ml on day 14, when
administered as topical composition once daily for 14 days.
[0211] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 160 pg/ml on day 1
post treatment, when administered as topical composition twice
daily for 14 days.
[0212] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 110 pg/ml on day 1 post
treatment, when administered as topical composition twice daily for
14 days.
[0213] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 225 pg/ml on day 7,
when administered as topical composition twice daily for 14
days.
[0214] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 150 pg/ml on day 7, when
administered as topical composition twice daily for 14 days.
[0215] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 315 pg/ml on day
14, when administered as topical composition twice daily for 14
days.
[0216] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 191 pg/ml on day 14, when
administered as topical composition twice daily for 14 days.
[0217] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 80 pg/ml on day 1
post treatment, when administered as topical composition once daily
for 14 days.
[0218] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 62 pg/ml on day 1 post
treatment, when administered as topical composition once daily for
14 days.
[0219] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 100 pg/ml on day 7,
when administered as topical composition once daily for 14
days.
[0220] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 66 pg/ml on day 7, when
administered as topical composition once daily for 14 days.
[0221] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, less than about 95 pg/ml on day 14,
when administered as topical composition once daily for 14
days.
[0222] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure (mean
C.sub.max) of tazarotenic acid, about 80 pg/ml on day 14, when
administered as topical composition once daily for 14 days.
[0223] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 2600
pgh/ml and mean C.sub.max less than about 160 pg/ml on day 1 post
treatment, when administered as topical composition twice daily for
14 days.
[0224] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 3900
pgh/ml and mean C.sub.max less than about 230 pg/ml on day 7, when
administered as topical composition twice daily for 14 days.
[0225] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 5600
pgh/ml and mean C.sub.max less than about 315 pg/ml on day 14, when
administered as topical composition twice daily for 14 days.
[0226] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 1690 pgh/ml
and mean C.sub.max about 110 pg/ml on day 1 post treatment, when
administered as topical composition twice daily for 14 days.
[0227] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 3550 pgh/ml
and mean C.sub.max about 150 pg/ml on day 7, when administered as
topical composition twice daily for 14 days.
[0228] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 4315 pgh/ml
and mean C.sub.max about 190 pg/ml on day 14, when administered as
topical composition twice daily for 14 days.
[0229] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 1200
pgh/ml and mean C.sub.max less than about 90 pg/ml on day 1 post
treatment, when administered as topical composition once daily for
14 days.
[0230] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 1550
pgh/ml and mean C.sub.max less than about 90 pg/ml on day 7, when
administered as topical composition once daily for 14 days.
[0231] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 less than about 1800
pgh/ml and mean C.sub.max less than about 100 pg/ml on day 14, when
administered as topical composition once daily for 14 days.
[0232] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 980 pgh/ml and
mean C.sub.max about 65 pg/ml on day 1 post treatment, when
administered as topical composition once daily for 14 days.
[0233] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 1250 pgh/ml
and mean C.sub.max about 65 pg/ml on day 7, when administered as
topical composition once daily for 14 days.
[0234] In an aspect, the topical composition of the present
application comprising tazarotene provides systemic exposure of
tazarotenic acid comprising: mean AUC.sub.0-24 about 1515 pgh/ml
and mean C.sub.max about 85 pg/ml on day 14, when administered as
topical composition once daily for 14 days.
[0235] In an aspect, the topical composition of the present
application comprising tazarotene, provides percentage ratio of
mean AUC.sub.0-24 of tazarotenic acid between twice daily to once
daily administration of topical composition, is from about 120% to
250% with 90% confidence limit on day 1 post treatment of 14 days
treatment.
[0236] In an aspect, the topical composition of the present
application comprising tazarotene, provides percentage ratio of
mean AUC.sub.0-24 of tazarotenic acid between twice daily of
topical composition to once daily TAZORAC.RTM. cream
administration, is from about 45% to 100% with 90% confidence limit
on day 1 post treatment of 14 days treatment.
[0237] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between once daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 20% to 55% with 90% confidence limit on day 1 post
treatment of 14 days treatment.
[0238] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between twice daily to once daily
administration of topical composition, is from about 200% to 350%
with 90% confidence limit on day 7 of 14 days treatment.
[0239] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between twice daily to once daily
TAZORAC.RTM. cream administration of topical composition, is from
about 60% to 150% with 90% confidence limit on day 7 of 14 days
treatment.
[0240] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between once daily to once daily
TAZORAC.RTM. cream administration of topical composition, is from
about 20% to 60% with 90% confidence limit on day 7 of 14 days
treatment.
[0241] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between once daily to twice daily
administration of topical composition, is from about 180% to 350%
with 90% confidence limit on day 14 of 14 days treatment.
[0242] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between twice daily to once daily
TAZORAC.RTM. cream administration of topical composition, is from
about 40% to 130% with 90% confidence limit on day 14 of 14 days
treatment.
[0243] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
AUC.sub.0-24 of tazarotenic acid between once daily to once daily
TAZORAC.RTM. cream administration of topical composition, is from
about 20% to 50% with 90% confidence limit on day 14 of 14 days
treatment.
[0244] In another aspect, twice daily minimum contact time
administration of topical composition of the present application
comprising tazarotene provides systemic exposure equivalent to that
of once-daily TAZORAC.RTM. administration.
[0245] In another aspect, twice daily minimum contact time
administration of topical composition of the present application
comprising tazarotene provides systemic exposure equivalent to that
of once-daily TAZORAC.RTM. cream administration.
[0246] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily to once daily
administration of topical compositions of present application, is
from about 130% to about 250% with 90% confidence limit on day 1
post treatment of 14 days treatment.
[0247] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between once daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 40% to about 100% with 90% confidence limit on day 1
post treatment of 14 days treatment.
[0248] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 20% to about 60% with 90% confidence limit on day 1 post
treatment of 14 days treatment.
[0249] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily to once daily
administration of topical compositions of present application, is
from about 170% to about 280% with 90% confidence limit on day 7 of
14 days treatment.
[0250] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between once daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 40% to about 120% with 90% confidence limit on day 7 of
14 days treatment.
[0251] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 20% to about 50% with 90% confidence limit on day 7 of
14 days treatment.
[0252] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily to once daily
administration of topical compositions of present application, is
from about 150% to about 300% with 90% confidence limit on day 14
of 14 days treatment.
[0253] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between once daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 40% to about 90% with 90% confidence limit on day 14 of
14 days treatment.
[0254] In an aspect, the topical composition of the present
application comprising tazarotene provides percentage ratio of mean
C.sub.max of tazarotenic acid between twice daily of topical
composition to once daily TAZORAC.RTM. cream administration, is
from about 20% to about 50% with 90% confidence limit on day 14 of
14 days treatment.
[0255] In an aspect, the topical composition of the present
application comprising tazarotene, provides retinoid activity at
par or more than TAZORAC.RTM. cream with minimum contact time less
than about 5 minutes.
[0256] In another aspects, the retinoid activity is correlated to
effect on skin barrier function, which is selected from
transepidermal water loss or exfoliation.
[0257] In another aspect, the topical composition comprising: a)
tazarotene; b) an anti-irritant; c) a foaming agent, and d) a
pharmaceutically acceptable excipient; wherein said composition
provides retinoid activity at application site with minimum period
of contact time, and said minimum period of contact time is less
than about 5 minutes.
[0258] In an aspect, the topical composition comprising: a)
tazarotene; b) an anti-irritant selected from polyhydroxy acids; c)
a foaming agent selected from disodium laureth sulfosuccinate,
cocobetaine, sodium lauryl sarcosinate, and sodium lauryl sulfate,
and d) a pharmaceutically acceptable excipient; wherein said
composition provides required retinoid activity at application site
with minimum period of contact time, and said minimum period of
contact time is less than about 5 minutes.
[0259] In an aspect, the topical composition of the present
application comprising tazarotene with minimum contact time less
than about 5 minutes, provides retinoid activity; wherein the
retinoid activity is increased transepidermal water loss as
compared to day 1 (baseline).
[0260] In another aspect, the transepidermal water loss increased
at least about 5% as compared to day 1 (baseline).
[0261] In another aspect, the transepidermal water loss increased
at least about 10% as compared to day 1 (baseline).
[0262] In another aspect, the transepidermal water loss increased
at least about 15% as compared to day 1 (baseline).
[0263] In another aspect, the transepidermal water loss increased
at least about 20% as compared to day 1 (baseline).
[0264] In another aspect, the transepidermal water loss increased
at least about 30% as compared to day 1 (baseline).
[0265] In an aspect, the topical composition of the present
application comprising tazarotene with minimum contact time less
than about 5 minutes, provides retinoid activity; wherein the
retinoid activity is increased exfoliation compared to day 1
(baseline).
[0266] In an aspect, the topical composition of the present
application comprising tazarotene with minimum contact time less
than about 5 minutes, provides retinoid activity; wherein the
retinoid activity increases transepidermal water loss compared to
TAZORAC.RTM. gel.
[0267] In an aspect, the topical composition of the present
application comprising tazarotene with minimum contact time less
than about 5 minutes, provides retinoid activity; wherein the
retinoid activity increases exfoliation compared to TAZORAC.RTM.
gel.
EXAMPLES
[0268] The following examples are provided to illustrate certain
specific aspects of the invention, and should not be construed to
limit the scope of the invention in any manner. The following
examples may include compilations of data that are representative
of data gathered at various times during the course of development
and experimentation related to the present invention.
[0269] In the examples, particle size of tazarotene was either
D90.apprxeq.10 .mu.m or .apprxeq.50 .mu.m.
[0270] Examples for retinoid-containing topical compositions:
Example 1
TABLE-US-00001 [0271] Ingredients % w/w Tazarotene 0.1 Sodium
lauryl sulfate 1.0 Stearyl alcohol 2.0 Cetyl alcohol 1.2
Gluconolactone 0.25 Glycerin 4.0 Tocofersolan 0.5 Carbopol 971P
0.25 Propyl paraben 0.03 Methyl paraben 0.20 Edetate disodium 0.1
Butylated Hydroxy Toluene 0.05 Caprylic/Capric Triglyceride 3.5
Triethanolamine q.s. to pH 6.3 Purified water q.s. to 100
[0272] Process of Preparation:
[0273] Preparation of aqueous phase: An aqueous phase was prepared
initially by adding together, a sufficient quantity of purified
water, glycerin, methyl paraben, galaconolactone, and edetate
disodium, under stirring to prepare a clear dispersion. Further,
carbopol 971P was added to this dispersion under homogenization,
and further,--sodium lauryl sulfate, at a concentration of around
90%, was added to this dispersion under homogenization, and the
temperature of the contents was maintained at 70.+-.5.degree.
C.
[0274] Preparation of oil phase: An oil phase was prepared by
mixing stearyl alcohol, cetyl alcohol, caprylic/capric
triglyceride, and tocofersolan, and these ingredients were melted
and stirred well, and further, propyl paraben and butylated
hydroxyl toluene were added to the above dispersion. Temperature of
the contents was maintained 70.+-.5.degree. C. throughout the
process. This oil phase was mixed slowly with aqueous phase under
homogenization to prepare the emulsion, and cooled down to
30.+-.2.degree. C. The pH of the emulsion was adjusted to
5.2.+-.0.2 by adding triethanolamine under homogenization.
[0275] Drug dispersion was prepared by adding tazarotene and
remainder of sodium lauryl sulfate to sufficient quantity of
purified water, by stirring. This drug dispersion was mixed with
the emulsion under homogenization. The pH of the product was then
adjusted to 6.3.+-.0.2 by adding triethanolamine solution, and the
final weight is made up with purified water.
Example 2
TABLE-US-00002 [0276] Ingredients % w/w Tazarotene 0.1 Sodium
Lauryl Sulfate 1.0 Stearyl alcohol 2.5 Cetyl alcohol 1.5
Gluconolactone 0.25 Glycerin 4.0 Tocofersolan 0.5 Carbopol 980 0.75
Propyl paraben 0.2 Methyl paraben 0.2 Triethanolamine q.s. to pH
6.3 Purified water q.s. to 100
[0277] Process of Preparation:
[0278] Preparation of aqueous phase: An aqueous phase was prepared
initially by adding together, a sufficient quantity of purified
water, glycerin, methyl paraben, glucaonolactone, and edetate
disodium under stirring to prepare a clear dispersion. Further,
carbopol 980 was added to this dispersion under homogenization, and
further, sodium lauryl sulfate, at a concentration of around 90%,
was added to this dispersion under homogenization. The temperature
of the contents was maintained at 70.+-.5.degree. C.
[0279] Preparation of oil phase: An oil phase was prepared by
mixing stearyl alcohol, cetyl alcohol, tocofersolan, and these
ingredients were melted and stirred well, and further, propyl
paraben was added to the above dispersion. The temperature of the
contents was maintained at 70.+-.5.degree. C. throughout the
process. This oil phase was mixed slowly with the aqueous phase
under homogenization to prepare the emulsion, and cooled down to
30.+-.2.degree. C. The pH of this emulsion was adjusted to
5.2.+-.0.2 by adding triethanolamine under homogenization.
[0280] Drug dispersion was prepared by adding tazarotene and
remainder of sodium lauryl sulfate to sufficient quantity of
purified water, by stirring. This drug dispersion was mixed with
emulsion under homogenization. The pH of the product was then
adjusted to 6.3.+-.0.2 by adding triethanolamine solution, and the
final weight is made up with purified water.
Example 3
TABLE-US-00003 [0281] Example 3A Example 3B Example 3C Ingredients
% w/w % w/w % w/w Tazarotene 0.10 0.10 0.10 Disodium Laureth 2.00
-- -- Sulfosuccinate Cocobetaine 3.00 3.00 -- Sodium Lauroyl --
2.00 -- Sarcosinate Sodium Lauryl Sulfate -- -- 1.00 Stearyl
Alcohol 2.00 2.00 -- Cetyl Alcohol 1.20 1.20 -- Gluconolactone 0.25
0.25 0.25 Tocofersolan 0.50 0.50 0.50 Glycerine 4.00 4.00 4.00
Carbomer 971 P 0.75 0.75 0.75 Propyl Paraben 0.03 0.03 0.20 Methyl
Paraben 0.20 0.20 0.20 Disodium Edetate 0.10 0.10 0.10 Butylated
Hydroxy 0.05 0.05 0.05 Toluene Caprylic/Capric 2.00 2.00 --
Triglyceride Triethanolamine q.s. to pH 6.3 q.s. to pH 6.3 q.s. to
pH 6.3 Purified Water q.s. to 100 q.s. to 100 q.s. to 100 Total
100.00 100.00 100.00
[0282] Process of Preparation:
[0283] Preparation of aqueous phase: An aqueous phase was prepared
initially by adding together, a sufficient quantity of purified
water, glycerin, methyl paraben, gluconolactone, and edetate
disodium, under stirring to prepare a clear dispersion. Further,
carbopol 971 P was added to this dispersion under homogenization,
and further, a foaming agent (either sodium lauryl sulfate, or
sodium lauroyl sarcosinate and cocobetaine, or disodium laureth
sulfosuccinate and cocobetaine), at a concentration of around 90%,
was added to this dispersion under homogenization. The temperature
of the contents was maintained at 70.+-.5.degree. C.
[0284] Preparation of oil phase: An oil phase was prepared by
mixing stearyl alcohol, cetyl alcohol, and tocofersolan, and these
ingredients were melted at 70.degree. C. and stirred, and further,
propyl paraben was added to the above dispersion. The temperature
of the ingredients was maintained at 70.+-.5.degree. C. throughout
this process. This oil phase was mixed slowly with the aqueous
phase under homogenization to prepare the emulsion, and cooled down
to 30.+-.2.degree. C. The pH of this emulsion was adjusted to
5.2.+-.0.2 by adding triethanolamine under homogenization.
[0285] Drug dispersion was prepared by adding tazarotene and
remainder of sodium lauryl sulfate to sufficient quantity of
purified water, by stirring. This drug dispersion was mixed with
the emulsion under homogenization. The pH of the product was then
adjusted to 6.3.+-.0.2 by adding triethanolamine solution and the
final weight is made up with purified water.
Example 4: Rat Skin Affinity Study
[0286] The retinoid-containing topical composition of the present
application shows skin deposition of retinoid compound and skin
affinity, in rat skin flap study. The rat skin flap study reveals
that the retinoid-containing topical composition of the present
application exhibits more skin affinity and therefore provides
desired retinoid compound deposition in the skin.
[0287] Rat Skin Affinity Study Protocol:
[0288] This protocol was used to examine the influence of
retinoid-containing topical compositions on skin affinity. Study
design and procedures were as follows:
[0289] The skin flaps of 50 cm.sup.2 (10 cm.times.5 cm) from dorsal
surface of SD/wistar rats were taken for each composition. The
weight of each skin flap also was recorded.
[0290] Total four retinoid-containing topical compositions were
evaluated. Total twelve skin flaps for four compositions (three
skin flaps per composition). Total four skin flaps for four placebo
compositions.
[0291] Application procedure: 10 ml of the composition
(active/placebo) was taken and 10 ml demineralized water was added
to it and mixed well to make lather and spread on the skin, and
immediately, this was washed off with 100 ml of demineralized
water. This procedure was repeated as follows: 2 applications in
first flap; 14 applications in second flap; 28 applications in
third flap; and fourth flap was for placebo composition. In case of
placebo composition, visual observation was made after 2, 14, and
28 application-washing cycles.
[0292] Observation: After completion of the study, the applied skin
flaps were visually inspected for changes in color and texture in
both drug and placebo treated skin flaps. An area of 4 cm.sup.2 of
skin pieces was separated from each skin flaps after subsequent
washes of 2, 14, 28, and each skin flap was analyzed, and
concentration of tazarotene was quantified by a sensitive UPLC/HPLC
method. The skin pieces were evaluated for deposition of tazarotene
in skin pores.
TABLE-US-00004 TABLE 1 Effect of Number of washes Vs. Tazarotene
deposition in skin No. of Tazarotene deposited Examples washes
(.mu.g)/gm of skin Example 1 2 20.48 14 31.14 28 44.11 Example 3A 2
26.11 14 21.98 28 16.01 Example 3B 2 6.94 14 15.94 28 21.45 Example
3C 2 19.81 14 33.08 28 35.12
[0293] In table 1, Example 1 and Example 3C were showing more skin
tazarotene deposition and continuous increase in tazarotene
deposition with increase in number of washes, while Example 3A and
3B were showing less tazarotene deposition. Example 1 showed linear
increase in tazarotene deposition, whereas Example 3C showed drug
deposition rate flat after 14 wash. In case of Example 3A,
tazarotene dislodging occurred because of cleansing effect of the
composition. In other words, Example 1 and 3C showed more skin
deposition of tazarotene in the skin.
Example 5: Two Weeks Skin Deposition Study in Neonatal Minipigs
[0294] Six neonatal minipigs were selected and the hair on the back
of the animals were clipped and divided into ten portions (4
cm.times.3 cm), and were wiped clean with water. All the animals
were anesthetized and the treatments were applied over an area of
12 cm.sup.2 within 15 seconds per massage. All the applied areas
were rinsed off with 20 ml of water after 5 minutes of the
application. The skin was then scored for visual appearance,
erythema and edema before application and after 1 h of removal of
composition (followed by Draize system of scoring). The same
treatment/irritancy scoring was repeated every 24 hours for two
weeks. After completion of the two weeks treatment cycle, the
treated skin was excised till subcutaneous fat and the skin was
further split into dermis and epidermis layers, and was transferred
into the extraction solvent. The tissue was then homogenized and
tazarotene was extracted. After centrifugation of the sample to
remove the cellular debris, the supernatant was analyzed for
tazarotene and its metabolite tazarotenic acid.
[0295] Each composition of Example 1 and Examples 3A, 3B and 3C
were prepared with two different particle sizes D90 is 10 .mu.m and
50 .mu.m, and they were called fraction 1 and fraction 2
respectively.
TABLE-US-00005 TABLE 2 The treatment groups are divided as follows:
Tazarotene Codes Treatment groups particle size (.mu.m) F1-1
Fraction1_Example 1 10 F2-1 Fraction2_Example 1 50 F1-3A
Fraction1_Example 3A 10 F2-3A Fraction2_Example 3A 50 F1-3B
Fraction1_Example 3B 10 F2-3B Fraction2_Example 3B 50 F1-3C
Fraction1_Example 3C 10 F2-3C Fraction2_Example 3C 50 Placebo
Control -- Reference TAZORAC gel --
TABLE-US-00006 TABLE 3 Percentage retention of Tazarotene and its
metabolite in epidermis (E) and dermis (D) Combined Combined (E +
D) Tazarotene Tazarotene (E + D) Tazarotenic Tazarotenic
Tazarotenic Compositions (E) (D) Tazarotene acid (E) acid (D) acid
F1-1 0.63 0.13 0.76 0.12 0.05 0.17 F2-1 0.70 0.15 0.85 0.13 0.03
0.16 F1-3A 0.85 0.41 1.26 0.16 0.21 0.36 F2-3A 0.27 0.07 0.34 0.1
0.07 0.16 F1-3B 0.9 0.11 1.02 0.05 0.05 0.10 F2-3B 0.35 0.09 0.44
0.07 0.02 0.09 F1-3C 0.44 0.31 0.75 0.06 0.03 0.09 F2-3C 0.35 0.06
0.41 0.08 0.01 0.09 TAZORAC 0.51 0.12 0.63 0.27 0.07 0.34
[0296] All the compositions showed similar tazarotene depositions
in epidermis and dermis which were equivalent or more than
reference product. Both fraction 1 and fraction 2 of example 1
exhibited comparable skin retention.
[0297] Tazarotene forms tazarotenic acid in dermis layer.
Tazarotenic acid is believed to cause irritation to the skin.
Epidermal degradation of tazarotene was lesser in the present
topical compositions than the reference product (TAZORAC). Thus all
the compositions of the present application provide higher skin
retention and lesser irritation to the skin.
Example 6: Skin Irritancy Study
[0298] The skin irritancy characteristics were evaluated by Draize
test and the evaluation was performed on all the compositions
listed in table 2. In Draize test, skin irritation was visually
evaluated based on appearance and severity of erythema, and all the
treatment sites were also evaluated microscopically.
[0299] Tazarotene of all the treatment groups had caused erythema.
The severity was lesser on the day 3 which then progressed to
moderate erythema from the days 6-8 and reversed to slight erythema
from the days 9-14. There was no obvious difference in skin
irritation pattern between all the treatment groups.
Example 7: Stability Studies
[0300] The prepared composition of example 1 was filled into closed
container and exposed to the stability testing conditions
25.degree. C. and 60% relative humidity (RH), 30.degree. C. and 65%
RH, and 40.degree. C. and 75% RH for nine months, and analyses at
various storage points are shown in Table 4.
TABLE-US-00007 TABLE 4 Stability testing of Example 1 Related
substances Storage Content Total Condition Assay Uniformity Imp A
Imp B Imp C SMI Impurities pH Acceptance 90.0- $ NMT NMT NMT NMT
NMT Viscosity 4.0- criteria 110.0% 1.0% 1.0% 1.0% 5.0% 0.5% # 7.0
Initial 101.2 Top-101.7 ND 0.18 ND ND 0.18 7048 5.99 Middle-100.9
Bottom-100.9 % RSD-0.45 1M 25.degree. C./ 99.5 Top-99.4 ND 0.25 ND
ND 0.31 6509 5.88 60% RH Middle-99.2 Bottom-99.9 % RSD-0.36 1M
40.degree. C./ 99.0 Top-98.9 ND 0.34 ND ND 0.34 6719 5.86 75% RH
Middle-99.0 Bottom-99.1 % RSD-0.10 2M 25.degree. C./ 98.7 NA ND
0.28 ND ND 0.28 7228 5.95 60% RH 2M 40.degree. C./ 98.1 NA ND 0.37
ND ND 0.37 6599 5.90 75% RH 3M 25.degree. C./ 101.2 Top-101.7 ND
0.45 ND ND 0.45 6449 5.93 60% RH Middle-101.0 Bottom-101.0 %
RSD-0.40 3M 30.degree. C./ 100.5 Top-100.5 ND 0.30 ND ND 0.30 7348
5.97 65% RH Middle-100.6 Bottom-100.3 % RSD-0.15 3M 40.degree. C./
98.9 Top-98.5 ND 0.64 ND ND 0.64 6419 5.92 75% RH Middle-99.0
Bottom-99.1 % RSD-0.33 6M 25.degree. C./ 98.5 Top-98.7 ND 0.48 ND
ND 0.48 5969 5.96 60% RH Middle-98.3 Bottom-98.5 % RSD-0.2 6M
30.degree. C./ 97.5 Top-97.5 ND 0.49 ND ND 0.49 4969 5.92 65% RH
Middle-97.5 Bottom-97.4 % RSD-0.1 6M 40.degree. C./ 96.5 Top-96.4
ND 0.69 ND ND 0.69 4169 5.85 75% RH Middle-96.6 Bottom-96.6 %
RSD-0.1 9M 25.degree. C./ 101.1 NA ND 0.86 ND ND 0.86 4409 5.87 60%
RH 9M 30.degree. C./ 99.0 NA ND 0.88 ND ND 0.88 3989 5.85 65% RH
12M 25.degree. C./ 95.9 Top-97.6 ND 0.51 ND ND 0.51 4679 5.79 60%
RH Middle-97.9 Bottom-98.0 RSD-0.2 12M 30.degree. C./ 95.9 Top-99.8
ND 0.57 ND ND 0.57 4229 5.83 65% RH Middle-99.7 Bottom-99.2 RSD-0.3
ND -- Not detected, SMI -- Single major unknown impurity NA -- Not
Applicable, # -- For Information $ -- The content of each sample is
between 90-110% of the label claim RSD of sample should not exceed
6%.
Example 8: Microscopy Data for Example 1
[0301] The compositions of Example 1 was examined by preparing 5%
solution of Triton X 100 in purified water. The composition was
dispersed in dispersion media, and the dispersion was measured for
its particle size and globule size.
TABLE-US-00008 TABLE 5 Microscopic observation of Example 1
Particle size Globule size of Tazarotene of oil Phase Condition D10
D50 D90 D10 D50 D90 Initial (batch 1) 3.5 4.3 8.2 3.4 5.5 8.7
Initial (batch 2) 4.2 5.4 15.0 4.1 6.2 8.9 Initial (batch 3) 3.8
4.9 12.3 3.5 5.4 8.3 Initial (batch 4) 3.8 5.7 12.9 3.9 6.0 8.8
Initial (batch 5) 3.8 6.1 14.2 3.8 5.7 8.9 24M 25.degree. C./60% RH
2.3 6.6 16.2 2.0 3.0 4.8
Example 9: Excipients Compatibility Study with Tazarotene
[0302] Excipient compatibility study for tazarotene was carried out
with various pharmaceutically acceptable excipients. The tazarotene
was tested in a set of compatibility screening studies with the
excipients in closed vials containing tazarotene. The excipients
physical mixture were incubated in ovens with and without moisture
at 60.degree. C. or 40.degree. C./75% RH for 4 weeks.
[0303] Conclusion: The result of the excipient compatibility study
had shown that tazarotene was incompatible with benzyl alcohol,
lactic acid, polysorbate 80. Tazarotene is compatible with
excipients of examples 1, 2, 3 such as carbomer polymer type A and
type B, cocobetaine, sodium lauryl sarcosinate, stearyl alcohol,
cetyl alcohol, glycerine, vitamin E TPGS, gluconolactone, butylated
hydroxytoluene, propylparaben, and methylparaben.
TABLE-US-00009 TABLE 6A Initial excipients compatibility S. No
Drug/Excipient Imp-A Imp-B Imp-C SMI Total imp 1. Tazarotene +
Lactic acid (0.1:18) ND 0.30 0.09 0.07 0.50 2. Tazarotene + Lactic
acid (0.1:9) ND 0.24 0.05 0.04 0.34 3. Tazarotene + Oleic acid
(0.1:25) ND 1.00 ND 0.05 1.05 4. Tazarotene + Oleic acid (0.1:12.5)
ND 1.00 ND 0.05 1.05 5. Tazarotene + Isostearic acid (0.1:25) ND
0.79 ND ND 0.79 6. Tazarotene + Isostearic acid (0.1:12.5) ND 1.23
ND ND 1.23 7. Tazarotene + Benzyl alcohol (0.1:2.7) ND 3.84 ND ND
3.84 8. Tazarotene + Benzyl alcohol (0.1:1.35) ND 1.84 ND ND 1.84
9. Tazarotene + Propylene Glycol (0.1:20) ND 0.43 ND ND 0.43 10.
Tazarotene + Propylene Glycol (0.1:10) ND 0.76 ND ND 0.76 11.
Tazarotene + Polysorbate 80 (0.1:15) ND 0.30 0.09 0.07 0.50 12.
Tazarotene + Polysorbate 80 (0.1:7.5) ND 0.24 0.05 0.04 0.34
TABLE-US-00010 TABLE 6B Excipients compatibility at 4 weeks
40.degree. C./75% RH S. No Drug/Excipient Imp-A Imp-B Imp-C SMI
Total imp 1. Tazarotene + Lactic acid (0.1:18) 0.13 0.85 0.83 3.18
12.18 2. Tazarotene + Lactic acid (0.1:9) 0.07 0.54 0.39 1.98 7.66
3. Tazarotene + Oleic acid (0.1:25) ND 1.98 ND ND 1.98 4.
Tazarotene + Oleic acid (0.1:12.5) ND 4.16 0.06 0.25 4.47 5.
Tazarotene + Isostearic acid (0.1:25) ND 4.69 0.05 ND 4.74 6.
Tazarotene + Isostearic acid (0.1:12.5) ND 2.59 0.07 ND 2.66 7.
Tazarotene + Benzyl alcohol (0.1:2.7) High degradation 8.
Tazarotene + Benzyl alcohol (0.1:1.35) 9. Tazarotene + Propylene
Glycol (0.1:20) ND 0.95 ND 0.23 1.27 10. Tazarotene + Propylene
Glycol (0.1:10) ND 1.54 0.21 0.11 1.87 11. Tazarotene + Polysorbate
80 (0.1:15) ND 31.45 ND 0.17 31.75 12. Tazarotene + Polysorbate 80
(0.1:7.5) ND 14.38 ND 0.06 14.44
TABLE-US-00011 TABLE 6C Excipients compatibility at 4 weeks
60.degree. C. S. No Drug/Excipient Imp-A Imp-B Imp-C SMI Total imp
1. Tazarotene + Lactic acid (0.1:18) 0.36 0.84 0.63 11.34 87.78 2.
Tazarotene + Lactic acid (0.1:9) 0.35 2.11 0.65 24.85 76.68 3.
Tazarotene + Oleic acid (0.1:25) ND 20.87 0.12 1.10 22.61 4.
Tazarotene + Oleic acid (0.1:12.5) ND 20.98 0.13 1.12 22.36 5.
Tazarotene + Isostearic acid (0.1:25) ND 16.93 0.13 0.43 17.60 6.
Tazarotene + Isostearic acid (0.1:12.5) ND 11.59 0.13 0.54 12.69 7.
Tazarotene + Benzyl alcohol (0.1:2.7) High degradation 8.
Tazarotene + Benzyl alcohol (0.1:1.35) 9. Tazarotene + Propylene
Glycol (0.1:20) ND 2.95 ND 1.66 5.58 10. Tazarotene + Propylene
Glycol (0.1:10) ND 2.96 ND 1.64 5.57 11. Tazarotene + Polysorbate
80 (0.1:15) ND 61.34 ND 0.73 62.49 12. Tazarotene + Polysorbate 80
(0.1:7.5) ND 75.40 ND 2.76 78.79
Example 10: Foaming Capacity Study
[0304] Compositions of Example 1, and Examples 3A, 3B, and 3C were
evaluated for foaming capacity. 5 gm of the compositions of Example
1 and Examples 3A, 3B, and 3C each were taken in a separate 100 ml
glass beakers, and 10 ml of purified water was added to the
beakers. The content of the beakers was allowed to stand for 30
minutes. The content of the beakers was stirred with a glass rod.
The dispersion/slurry was transferred to a 250 ml measuring
cylinder and no foam was produced while transferring the content.
The volume was adjusted up to 50 ml of the measuring cylinder by
adding water, and the contents of the cylinder was brought to
30.degree. C. After the contents reached 30.degree. C., the
contents were given 12 complete shake. The shake action was
performed as measuring cylinder was closed and inverted to 180
degree down and restored back to normal position. This shake action
was performed 12 times. After the shake, the contents were allowed
to stand for 5 minutes. The foam capacity was calculated as
follows: a) foam plus water (V.sub.1 ml), and b) water only
(V.sub.2 ml). The foaming capacity is in ml=V.sub.1-V.sub.2.
[0305] Results: The foam generated for example 1 was in the range
of 10 ml to 34 ml, in case of example 3A, 3B, and 3C compositions
provided 10 ml to 102 ml of foam. The high foaming capacity was
seen in example 3C which provided 103 ml of foam.
Example 11: Tazarotene Composition and Study on Stability of
Tazarotene in Different pH
TABLE-US-00012 [0306] S. No Ingredients % w/w 1. Tazarotene 0.10 2.
Sodium Lauryl Sulfate 1.00 3. Gluconolactone 0.25 4. Tocofersolan
0.50 5. Glycerine 4.00 6. Carbomer 971 P 0.75 7. Propyl Paraben
0.20 8. Methyl Paraben 0.20 9. Disodium Edetate 0.10 10. Butylated
Hydroxy 0.05 Toluene 11. Caprylic/Capric 2.0 Triglyceride 12.
Triethanolamine q.s. 13. Purified Water q.s. to 100 Total
100.00
[0307] Manufacturing Process:
[0308] The above composition was prepared by a process denoted in
example 1 till emulsification. The emulsified base was neutralized
to following pH:
TABLE-US-00013 Emulsified pH of emulsified base pH of the base
(pre-neutralization) composition Part 1 3.2 3.01 Part 2 4.65 4.59
Part 3 5.45 5.26 Part 4 6.39 6.31
[0309] Tazarotene phase was added separately to these four parts of
emulsified base and homogenized as mentioned in Example 1 process
and pH of the composition was adjusted. The composition was
evaluated for stability for about 2 months.
TABLE-US-00014 TABLE 7 Stability results of Example 11 Composition
Condition Related substances (RS) % RS Initial Impurity A ND
Composition Impurity B 0.49 of Part 1 Impurity C ND SMI ND Total
impurities 0.49 2 months, Impurity A 0.22 45.degree. C. Impurity B
1.62 Impurity C 1.25 SMI 1.46 Total impurities 8.81 Composition
Initial Impurity A ND of Part 2 Impurity B 0.33 Impurity C ND SMI
ND Total impurities 0.33 2 months, Impurity A 0.01 45.degree. C.
Impurity B 0.38 Impurity C 0.06 SMI 0.05 Total impurities 0.52
Composition Initial Impurity A ND of part 3 Impurity B 0.24
Impurity C ND SMI ND Total impurities 0.24 2 months, Impurity A
0.01 45.degree. C. Impurity B 0.38 Impurity C 0.03 SMI ND Total
impurities 0.52 Composition Initial Impurity A ND of Part 4
Impurity B 0.24 Impurity C ND SMI ND Total impurities 0.24 2
months, Impurity A 0.01 45.degree. C. Impurity B 0.41 Impurity C
0.08 SMI 0.08 Total impurities 0.66
[0310] Physical observation: The Composition of part 1, 2, 3 and 4
were observed to be complete yellow, off white, white and white
respectively at 2 months, 45.degree. C. The final composition of
part 3 and 4 were finalized due its physical and chemical
stability.
Example 12: Multiple Dose Bioavailability Study of Tazarotene
Composition 0.1% of Example 1 Versus TAZORAC.RTM. 0.1% Cream
[0311] Study design: The study was a single-center, randomized,
multiple dose, laboratory-blinded, open-label, 3-arm, parallel
design in healthy male subjects. The following investigational
products were to be administered: 1) Test product: composition of
example 1 (tazarotene 0.1%) and 2) reference: TAZORAC cream 0.1%.
Following were treatment arms: 1) Treatment 1: Test product applied
twice daily, in the morning and evening, 12 hours apart; 2)
Treatment 2: Test product applied once daily, in the morning; and
3) Treatment 3: Reference product applied once daily, in the
morning. For each study arm (n=16), approximately 5 g of the Test
or Reference product was to be applied to the subjects face, neck,
shoulders, upper chest and upper back (total approximately
equivalent to 15% body surface area (BSA)) over 14 consecutive days
(Days 1 to 14). Blood sample were collected time to time as per the
schedule of the study.
[0312] Conclusion: Very low concentrations of the parent compound,
tazarotene, were detected in plasma samples. Following topical
application, tazarotene undergoes rapid esterase hydrolysis to its
primary active metabolite, tazarotenic acid, and typically little
parent compound is detected in plasma.
[0313] The exposure to tazarotenic acid was more than 2 times
higher when the example 1 composition was applied as a lotion twice
daily (Treatment-1) compared to a once daily application
(Treatment-2). This indicates linear pharmacokinetics between once
a day versus twice a day application.
[0314] It appears that following multiple applications of the
example 1 composition, the exposure (AUC.sub.0-24) to tazarotenic
acid could be similar when compared to the multiple applications of
the cream.
TABLE-US-00015 TABLE 8 Summary of plasma tazarotenic acid
pharmacokinetic parameters day 1 Treatment 1 Treatment 2 Treatment
3 Coefficient Coefficient Coefficient variation variation variation
Parameters (units) Mean (CV) % Mean (CV) % Mean (CV) % Mean
C.sub.max ((pg/ml) 108 30.4 63 58.8 159 38.2 T.sub.max (hours) 18
1-23.92 12 1-23.92 12 8-11.92 Mean AUC.sub.0-12 (pg h/ml) 548 43.7
NA NA NA NA Mean AUC.sub.0-24 (pg h/ml) 1688 31.9 978 42.5 2546
36.2 NA: Not applicable
TABLE-US-00016 TABLE 9 Summary of Plasma Tazarotenic acid
pharmacokinetic parameters-Day 7 Treatment 1 Treatment 2 Treatment
3 Coefficient Coefficient Coefficient variation variation variation
Parameters (units) Mean (CV) % Mean (CV) % Mean (CV) % Mean
C.sub.max (pg/ml) 150 41.2 66 24.4 225 68.7 T.sub.max (hours) 8
4-11.92 8 6-11.92 8 5.92-11.95 Mean AUC.sub.0-12 (pg h/ml) 1644
40.6 NA NA NA NA Mean AUC.sub.0-24 (pg h/ml) 3512 39.6 1270 25.3
3875 57.7 NA: Not applicable
TABLE-US-00017 TABLE 10 Summary of Plasma Tazarotenic acid
pharmacokinetic parameters-Day 14 Treatment 1 Treatment 2 Treatment
3 Coefficient Coefficient Coefficient variation variation variation
Parameters (units) Mean (CV) % Mean (CV) % Mean (CV) % Mean
C.sub.max ((pg/ml) 191 65.9 79 20.1 313 63.5 T.sub.max (hours) 5
0-8.0 8 2-11.92 8 6-12 Mean AUC.sub.0-12 (pg h/ml) 2038 63.2 NA NA
NA NA Mean AUC.sub.0-24 (pg h/ml) 4312 58.3 1515 17.2 5408 56.8 NA:
Not applicable
Example 13: Comparison of TAZORAC (Tazarotene 0.1%) Gel to Example
1, on Changes in Transepidermal Water Loss on the Face
[0315] Twenty-four (24) subjects were enrolled into this study.
Example 1, 0.1% and Vehicle (Placebo) composition were applied
twice daily to test sites on the subject's face. The Example 1
composition and Vehicle composition were removed after 1 minute
with water dampened cotton balls. TAZORAC.RTM. gel, 0.1% was
applied once daily and removed after 5 minutes with water dampened
cotton balls. The study product application was repeated for 21
consecutive days.
[0316] The forehead sites received the TAZORAC.RTM. gel and Example
1 (one side each), one cheek received the Vehicle Lotion and the
other cheek served as an untreated control. Test sites were treated
with 2.5 uL/cm.sup.2 of study product. Subjects washed their face
with Cetaphil Daily Facial Cleanser twice daily, not less than 60
minutes prior to test site evaluations. All test sites were
assessed for transepidermal water-loss (TEWL) using an evaporimeter
and visually scored for exfoliation in the morning before study
product application.
[0317] Transepidermal water loss score: TEWL at the treated sites
was measured once daily in the morning before study product
application and at least 60 minutes after any face washing.
[0318] Exfoliation score: Test sites were scored once daily for
exfoliation (scored as 0=none, 1=scaling/peeling in a small portion
of the test site, 2=up to one-half of the site peeling or having
peeled, 3=over one half of the site peeling or having peeled).
Across all products, mean daily scores ranged from 0 to 0.2. The
daily scores were summed for a total score for each subject and
study products compared.
[0319] Conclusion: Upon topical treatment with many retinoids, a
physiological change occurs in the stratum corneum exfoliation
process leading to a reduction in its barrier properties as
evidenced by increased TEWL (Lehman, 2013). Often accompanying this
increase in TEWL is transient accelerated exfoliation (e.g.
peeling) and mild irritation. Based on the results of this study,
Example 1 appeared to have significant retinoid activity when
applied to the forehead for 1 minute and then wiped off for 21
consecutive days. This was indicated by the TEWL readings that were
significantly increased compared to Vehicle-treated sites and were
similar to the TAZORAC.RTM. gel treated sites. TAZORAC.RTM. gel was
left on the forehead sites for 5 minute and then wiped off.
Exfoliation were less than expected with most all subjects
experiencing no irritation or exfoliation for either retinoid
containing product. Despite the minimal levels of erythema,
significantly more erythema was observed on the cheek test sites
than the forehead test sites.
TABLE-US-00018 TABLE 11 Mean total exfoliation score: Example 1
composition TAZORAC .RTM. Vehicle Untreated Product Forehead gel
Cheeks Forehead Cheeks Mean total score 2.2 1.7 1 0.2 Standard
deviation 7.3 6.6 2.2 0.5 p value vs Vehicle* 0.445 0.624 *p-value
from Student's t-test.
TABLE-US-00019 TABLE 12 Transepidermal water loss score TAZORAC
.RTM. Example 1 Vehicle gel composition composition Untreated Day
Mean SD Mean SD Mean SD Mean SD 1 18.2 3.3 18.3 3.5 17.1 3.4 17.1
3.4 2 18.3 4.6 18.7 4.5 17.9 4 17.2 4.4 3 21.0 4.4 22.7 6.8 19.9
4.6 19.9 5 4 19.8 4.4 23.1 8.3 20.1 5.7 19.8 4.9 5 23.2 7.2 25 14.3
22.4 6.8 21.6 6.1 6 24.7 10.3 24.6 9.3 21.6 4.3 20.1 4.5 7 24.9 5.5
30 12 22.9 3.8 22.2 4.7 8 26.1 8.8 30.9 10.8 22.8 3.3 21 3.3 9 25.3
6.0 28.7 9.1 22.2 4.1 21 3.9 10 25.9 7.3 29.7 8 23 4.6 20.8 4.4 11
25.0 7.3 28.2 8.6 22.6 3.4 20.7 4.4 12 24.4 7.5 26.9 7.6 21.9 3.6
20.2 4.6 13 27.6 8.7 31.4 10.7 24.5 4.5 23.6 5.4 14 26.2 9.8 28.9
6.2 22.9 4.1 21.4 3.7 15 29.2 12.9 32 8.8 25.8 6.2 23.7 5.6 16 26.3
9.6 31.5 10.6 22.8 4.4 21.7 4 17 23.7 6.4 27.4 6.2 21.9 3.8 20.6
4.3 18 27.0 14.7 27.9 8.9 21.8 3.8 20.7 4.3 19 26.2 9.6 28.9 9.6
21.3 3.4 20.3 4 20 25.5 8.2 27.1 9.2 21.4 3.6 20.9 4.6 21 25.5 8.3
25.9 8.8 22.1 4.2 20.1 3.5 22 23.8 8.5 25.9 9.6 19.5 4.1 18.5
3.2
[0320] Throughout this document, various references are mentioned.
All such references are incorporated herein by reference.
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